Biphenyl compound

ABSTRACT

A novel biphenyl compound having GPR 14 antagonistic activity. It is a compound represented by the formula (I): 
                         
wherein R 1  represents hydrogen, etc.; X represents 1 to 12 spacers; A represents amino, etc., R 2  and R 3  each represents a hydrocarbon group, etc.; and rings B and C each represents an optionally further substituted benzene ring, or a salt thereof.

This application is the national phase of PCT/JP01/05541 filed 28 Jun.2001.

TECHNICAL FIELD

The present invention relates to novel biphenyl compounds having GPR14-antagonizing activity or somatostatin receptor function regulatoryactivity, or salts thereof, and their use.

BACKGROUND OF THE INVENTION

Urotensin II was discovered as one of peptide hormones having a potentvasoconstrictive activity, and has been proved to have far highervasoconstrictive activity than endothelin, which is the most potentvasoconstrictor among those which are currently known to havevasoconstrictive activity on mammal arteria. Further, it has beenrevealed that the receptor for urotensin II is GPR 14 protein, which isone of the orphan receptors (see, Nature, vol. 401, p. 282 (1999)).

On the other hand, somatostatin has been isolated and identified fromsheep hypothalamus tissue as a factor for strongly suppressing secretionof growth hormone and is a peptide composed of 14 amino acids (SST-14).At present, somatostatin composed of 28 amino acids (SST-28) is alsoisolated and identified. This somatostatin is a brain-gut peptide widelydistributed in not only hypothalamus, but also in brain, limbic system,spinal cord, vagus nerve, autonomic neuroganglion, gastrointestinalmucosa, pancreas Langerhans islets, etc., and suppresses secretion ofpituitary-gastrointestinal hormones such as growth hormone, thyroidstimulating hormone, gastrin, insulin, glucagon, etc. Further, itsuppresses secretion of gastric juice, pancreatic exocrine, andgastrointestinal movement and blood flow. As somatostatin receptors, upto the present, type 1 to type 5 (SSTR1, SSTR2, SSTR3, SSTR4, SSTR5)have been known and it is recognized that each of them shows differentexpression.

-   [1. Life Science, Vol. 57, No. 13, p. 1249 (1995)-   2. Journal of Clinical Endocrinology and Metabolism, Vol. 80, No. 6,    pp. 1789–1793-   3. The New England Journal of Medicine, Jan. 25, 1996-   4. Eur. J. Clin. Pharmacol., 1996, 51, 139–144-   5. Exp. Opin. Ther. Patents (1998) 8 (7): 855–870]

As compounds having somatostatin receptor regulating activity, there arepeptide compounds described in Life Science, 31, 1133–1140 (1982),Nature, 292, 55–58 (1981) and the like; and non peptide compoundsdescribed in JP 2000-191615 A, JP 2000-191648 A, JP 2000-226373 A, JP11-209356 A and the like. As compounds having somatostatin receptorregulating activity and containing biphenyl in their structures, thereare compounds described in JP 2000-226373 and the like.

Further, as biphenyl compounds, for example, JP 6-107649 A disclosesbiphenyl compounds having 5-HT (serotonin) receptor antagonisticactivity and its Example 10 discloses4′-[[(methoxyacetyl)methylamino]methyl]-N-[4-methoxy-3-(4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-[1,1′-biphenyl}-4-carboxamidehydrochloride.

SUMMARY OF THE INVENTION

An antagonist of urotensin II receptor GPR 14 may possibly be developedas a novel vasoactive drug (a therapeutic agent for treating ischemicmyocardial infarction, congestive heart failure and the like). However,none of such antagonists have been reported yet.

The present invention provides novel biphenyl compounds having GPR14-antagonizing activity or somatostatin receptor function regulatoryactivity, or salts thereof and, based on GPR 14-antagonizing activity, avasoactive agent, in particular, a vasoconstriction inhibitor which isuseful for preventing and/or treating, for example, hypertension,arteriosclerosis, hypercardia, myocardial infarction, heart failure andthe like. Further, based on somatostatin receptor function regulatoryactivity, it provides an agent for preventing and/or treating diabetes,obesity, diabetic complication, intractable diarrhea, glaucoma,acromegaly, depression, tumor and the like.

The present inventors have intensively examined compounds having GPR14-antagonizing activity or somatostatin receptor function regulatoryactivity. As a result, it has been found that a compound having theformula (I) below or salts thereof (hereinafter sometimes referred to as“compound (I)”) can exhibit an excellent GPR 14-antagonizing activity orsomatostatin receptor function regulatory activity. Thus, the presentinvention has been completed.

The present invention relates to:

1) A compound represented by the formula (I):

wherein R¹ represents hydrogen atom or an optionally substitutedhydrocarbon group; X represents a spacer whose linear chain moiety iscomposed of 1 to 12 atoms; R¹ and X may be bound to each other to form aring; A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group; R²represents an optionally substituted hydrocarbon group or an optionallysubstituted amino group; R³ represents an optionally substitutedhydrocarbon group; and rings B and C each represents a furtheroptionally substituted benzene ring, or a salt thereof, provided that(1) a compound represented by the formula:

wherein each symbol is as defined above and (2)4′-[[(methoxyacetyl)methylamino]methyl]-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-[1,1′-biphenyl]-4-carboxamideare excluded;

2) A compound represented by formula (I):

wherein R¹ represents hydrogen atom or an optionally substitutedhydrocarbon group; X represents a spacer whose linear chain moiety iscomposed of 1 to 8 atoms; R¹ and X may be bound to each other to form aring; A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group; R² and R³each represent an optionally substituted hydrocarbon group, and rings Band C each represent a further optionally substituted benzene ring, or asalt thereof, provided that4′-[[(methoxyacetyl)methylamino]methyl]-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-[1,1′-biphenyl]-4-carboxamideis excluded;

3) The compound according to the above 2), which is represented by theformula (I):

wherein R¹ represents a hydrogen atom or an optionally substitutedhydrocarbon group, X represents a spacer whose linear chain moiety iscomposed of 1 to 8 atoms, R¹ and X may be bound to each other to form aring, A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group, R² and R³each represents an optionally substituted hydrocarbon group, and rings Band C each represents a further optionally substituted benzene ring, ora salt thereof, provided that a compound represented by the formula:

wherein each symbol is as defined above, is excluded;

4) The compound according to the above 1), wherein R¹ is (1) hydrogenatom; (2) C₁₋₁₀alkyl which may have 1 to 3 substituents selected from(1′) halogen atom, (2′) nitro, (3′) cyano, (4′) oxo, (5′) hydroxylgroup, (6′) thiol, (7′) C₁₋₄alkylthio, (8′) amino group, (9′)mono-C₁₋₄alkylamino, (10′) di-C₁₋₄alkylamino, (11′) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, 2-oxo-1-pyrrolidinyl and2-oxo-1-piperidinyl, (12′) phenyl-C₁₋₄alkyl, (13′) C₃₋₇cycloalkyl, (14′)carboxyl, (15′) C₁₋₄alkoxy-carbonyl, (16′) C₇₋₁₀aralkyloxy-carbonyl,(17′) carbamoyl, (18′) mono-C₁₋₄alkylcarbamoyl, (19′)di-C₁₋₄alkylcarbamoyl, (20′) C₁₋₄alkyl which may be substituted with ahalogen atom or C₁₋₄alkoxy, (21′) C₁₋₄alkoxy which may be substitutedwith a halogen atom or C₁₋₄alkoxy, (22′) C₁₋₄alkylenedioxy, (23′)formyl, (24′) C₂₋₄alkanoyl, (25′) C₁₋₄alkylsulfonyl, (26′)C₁₋₄alkylsulfinyl, (27′) sulfamoyl, (28′) mono-C₁₋₄alkylsulfamoyl, (29′)di-C₁₋₄alkylsulfamoyl, (30′) C₆₋₁₄aryl (which may be substituted with asubstituent(s) selected from (1″) halogen, (2″) nitro, (3″) cyano, (4″)hydroxyl group, (5″) thiol, (6″) C₁₋₄alkylthio, (7″) amino, (8″)mono-C₁₋₄alkylamino, (9″) di-C₁₋₄alkylamino, (10″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (11″)phenyl-C₁₋₄alkyl, (12″) C₃₋₇cycloalkyl, (13″) carboxyl group, (14″)C₁₋₄alkoxy-carbonyl, (15″) C₇₋₁₀aralkyloxy-carbonyl, (16″) carbamoyl,(17″) mono-C₁₋₄alkyl-carbamoyl, (18″) di-C₁₋₄alkyl-carbamoyl, (19″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(20″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (21″) C₁₋₄alkylenedioxy, (22″) formyl, (23″) C₂₋₄alkanoyl,(24″) C₁₋₄alkylsulfonyl, (25″) C₁₋₄alkylsulfinyl, (26″) sulfamoyl, (27″)mono-C₁₋₄alkylsulfamoyl, (28″) di-C₁₋₄alkylsulfamoyl and (29″) 5- to6-membered aromatic monocyclic heterocyclic group), and (31′) 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom(said heterocyclic group may have 1 to 3 substituents selected from (1″)halogen, (2″) nitro, (3″) cyano, (4″) oxo, (5″) hydroxyl group, (6″)thiol, (7″) C₁₋₄alkylthio, (8″) amino, (9″) mono-C₁₋₄alkylamino, (10″)di-C₁₋₄alkylamino, (11″) 5- to 6-membered cyclic amino selected fromtetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole and imidazole, (12″) phenyl-C₁₋₄alkyl, (14″) C₃₋₇cycloalkyl,(15″) carboxyl, (16″) C₁₋₄alkoxy-carbonyl, (17″)C₇₋₁₀aralkyloxy-carbonyl, (18″) carbamoyl, (19″)mono-C₁₋₄alkyl-carbamoyl, (20″) di-C₁₋₄alkyl-carbamoyl, (21″) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (22″)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(23″) C₁₋₄alkylenedioxy, (24″) formyl, (25″) C₂₋₄alkanoyl, (26″)C₁₋₄alkylsulfonyl, and (27″) C₁₋₄alkylsulfinyl) (hereinafter referred toas substituent group A); (3) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group A; (4) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupA; (5) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group A; (6) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group A; (7) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group A; (8)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group A; (9) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group A; (10)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (11) a group represented by the formula—X′″—G—(CH₂)_(n)—J wherein X′″ represents C₁₋₄alkylene orC₂₋₄alkenylene, G is a bond, —O—, —S—, —CO—NH— or —NH—CO—, n is aninteger of 0 to 3, J represents (a) C₆₋₁₄aryl (which may have 1 to 3substituents selected from (1″) halogen, (2″) nitro, (3″) cyano, (4″)hydroxyl group, (5″) thiol, (6″) C₁₋₄alkylthio, (7″) amino, (8″)mono-C₁₋₄alkylamino, (9″) di-C₁₋₄alkylamino, (10″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, 2-oxo-1-pyrrolidinyl and2-oxo-1-piperidinyl, (11″) phenyl-C₁₋₄alkyl, (12″) C₃₋₇cycloalkyl, (13″)carboxyl, (14″) C₁₋₄alkoxy-carbonyl, (15″) C₇₋₁₀aralkyloxy-carbonyl,(16″) carbamoyl, (17″) mono-C₁₋₄alkyl-carbamoyl, (18″)di-C₁₋₄alkyl-carbamoyl, (19″) C₁₋₄alkyl which may be substituted with ahalogen atom or C₁₋₄alkoxy, (20″) C₁₋₄alkoxy which may be substitutedwith a halogen atom or C₁₋₄alkoxy, (21″) C₁₋₄alkylenedioxy, (22″)formyl, (23″) C₂₋₄alkanoyl, (24″) C₁₋₄alkylsulfonyl, (25″)C₁₋₄alkylsulfinyl, (26″) sulfamoyl, (27″) mono-C₁₋₄alkylsulfamoyl, (28″)di-C₁₋₄alkylsulfamoyl, (29″) C₆₋₁₄aryl (which may be substituted with asubstituent(s) selected from (1′″) halogen, (2′″) nitro, (3′″) cyano,(4′″) hydroxyl group, (5′″) thiol, (6′″) C₁₋₄alkylthio, (7′″) amino,(8′″) mono-C₁₋₄alkylamino, (9′″) di-C₁₋₄alkylamino, (10′″) 5- to6-membered cyclic amino selected from tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole and imidazole, (11′″)phenyl-C₁₋₄alkyl, (12′″) C₃₋₇cycloalkyl, (13′″) carboxyl group, (14′″)C₁₋₄alkoxy-carbonyl, (15′″) C₇₋₁₀aralkyloxy-carbonyl, (16′″) carbamoyl,(17′″) mono-C₁₋₄alkyl-carbamoyl, (18′″) di-C₁₋₄alkyl-carbamoyl, (19′″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(20′″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (21′″) C₁₋₄alkylenedioxy, (22′″) formyl, (23′″)C₂₋₄alkanoyl, (24′″) C₁₋₄alkylsulfonyl, (25′″) C₁₋₄alkylsulfinyl, (26′″)sulfamoyl, (27′″) mono-C₁₋₄alkylsulfamoyl, (28′″) di-C₁₋₄alkylsulfamoyl,and (29′″) 5- to 6-membered aromatic monocyclic heterocyclic group), and(30″) 5- to 8-membered aromatic heterocyclic group or saturated orunsaturated non-aromatic heterocyclic group containing at least one of 1to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom (said heterocyclic group may have 1 to 3 substituentsselected from (1′″) halogen, (2′″) nitro, (3′″) cyano, (4′″) oxo, (5′″)hydroxyl group, (6′″) thiol, (7′″) C₁₋₄alkylthio, (8′″) amino, (9′″)mono-C₁₋₄alkylamino, (10′″) di-C₁₋₄alkylamino, (11′″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (12′″)phenyl-C₁₋₄alkyl, (13′″) C₃₋₇cycloalkyl, (14′″) carboxyl, (15′″)C₁₋₄alkoxy-carbonyl, (16′″) C₇₋₁₀aralkyloxy-carbonyl, (17′″) carbamoyl,(18′″) mono-C₁₋₄alkyl-carbamoyl, (19′″) di-C₁₋₄alkyl-carbamoyl, (20′″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(21′″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (22′″) C₁₋₄alkylenedioxy, (23″) formyl, (24′″) C₂₋₄alkanoyl,(25′″) C₁₋₄alkylsulfonyl and (26′″) C₁₋₄alkylsulfinyl) (hereinafterreferred to as substituent group B), or (b) a 5- to 8-membered aromaticheterocyclic group containing at least one of 1 to 3 kinds ofheterocyclic groups selected from oxygen atom, sulfur atom and nitrogenatom (said aromatic heterocyclic group optionally having 1 to 3substituents selected from the substituent group B); or (12) a grouprepresented by the formula —X″″—L—(CH₂)_(n)—M wherein X″″ represents abond or a C₁₋₄alkylene group which may have 1 to 3 substituents selectedfrom the substituent group A, L represents (a) a bond, (b) C₆₋₁₀arylwhich may have 1 to 3 substituents selected from the substituent groupB, (c) a 5- to 8-membered aromatic heterocyclic group containing atleast one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom (said aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup B), (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—, n is an integerof 0 to 3, and M represents amino group, guanidino group, sulfamoylgroup, carbamoyl group or hydroxyl group,

X represents the following saturated divalent groups wherein some bondsmay have been converted into unsaturated bonds:

(1) —(CH₂)_(f1)—, wherein f1 represents an integer of 1 to 12,

(2) —(CH₂)_(g1)—X¹—(CH₂)_(g2)—, wherein g1 and g2 are the same ordifferent, and represent an integer of 0 to 11, provided that the sum ofg1 and g2 is 0 to 11, and X¹ represents NH, O, S, SO or SO₂, or

(3) —(CH₂)_(h1)—X¹—(CH₂)_(h2)—X²—(CH₂)_(h3)— wherein h1, h2 and h3 arethe same or different, and represent an integer of 0 to 10, providedthat the sum of h1, h2 and h3 is 0 to 10, and X¹ and X² each representsNH, O, S, SO or SO₂ provided that when h2 is 0, X¹ and/or X² preferablyrepresent NH,

A represents (1) (a) C₁₋₁₀alkyl which may have 1 to 3 substituentsselected from (1″) halogen, (2″) nitro, (3″) cyano, (4″) oxo, (5″)hydroxyl group, (6″) thiol, (7″) C₁₋₄alkylthio, (8″) amino, (9″)mono-C₁₋₄alkylamino, (10″) di-C₁₋₄alkylamino, (11″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (12″)phenyl-C₁₋₄alkyl, (13″) C₃₋₇cycloalkyl, (14″) carboxyl, (15″)C₁₋₄alkoxy-carbonyl, (16″) C₇₋₁₀aralkyloxy-carbonyl, (17″) carbamoyl,(18″) mono-C₁₋₄alkyl-carbamoyl, (19″) di-C₁₋₄alkyl-carbamoyl, (20″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(21″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (22″) C₁₋₄alkylenedioxy, (23″) formyl, (24″) C₂₋₄alkanoyl,(25″) C₁₋₄alkylsulfonyl and (26″) C₁₋₄alkylsulfinyl (hereinafterreferred to as substituent group C), (b) C₃₋₈cycloalkyl which may have 1to 3 substituents selected from the substituent group C, (c)C₂₋₁₀alkenyl which may have 1 to 3 substituents selected from thesubstituent group C, (d) C₃₋₈cycloalkenyl which may have 1 to 3substituents selected from the substituent group C, (e) C₂₋₁₀alkynylwhich may have 1 to 3 substituents selected from the substituent groupC, (f) C₆₋₁₄aryl which may have 1 to 3 substituents selected from thesubstituent group C, (g) C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group C, (h)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group C, (i) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group C, (j) a 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom,which may have 1 to 3 substituents selected from the substituent groupC, (k) acyl selected from formyl, C₁₋₁₀alkyl-carbonyl,C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup C), or (l) amino which may have 1 to 2 substituents selected fromacyl groups wherein a 5- to 8-membered aromatic heterocyclic group orsaturated or unsaturated non-aromatic heterocyclic group containing aleast one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom has been bound to carbonyl or sulfonyl(said acyl optionally having 1 to 3 substituents selected from thesubstituent group C); or (2) cyclic amino which may have 1 to 3substituents selected from (a) halogen, (b) nitro, (c) cyano, (d)hydroxyl group, (e) thiol, (f) amino, (g) carboxyl, (h) optionallyhalogenated C₁₋₄alkyl, (i) optionally halogenated C₁₋₄alkoxy, (j)formyl, (k) C₂₋₄alkanoyl and (1) C₁₋₄alkylsulfonyl; or (3) a groupformed by removing one hydrogen atom from a 5- to 8-membered aromaticmonocyclic heterocyclic ring or saturated or unsaturated non-aromaticmonocyclic heterocyclic group containing one nitrogen atom and one tothree kinds of 1 to 4 heteroatoms selected from oxygen atom, sulfur atomand nitrogen atom or by removing one hydrogen atom from a ring wherein 2or 3 the same or different rings selected from the above monocyclicrings have been fused (said heterocyclic group optionally having 1 to 3substituents selected from the substituent group C),

R² represents (1) C₁₋₁₀alkyl which may have 1 to 3 substituents selectedfrom the substituent group A; (2) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group A; (3) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupA; (4) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group A; (5) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group A; (6) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group A; (7)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group A; (8) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group A; (9)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (10) a group represented by the formula—X′″—G—(CH₂)_(n)—J, wherein X′″ represents C₁₋₄alkylene orC₂₋₄alkenylene, G represents a bond, —O—, —S—, —CO—NH— or —NH—CO—, n isan integer of 0 to 3, and J represents (a) C₆₋₁₄aryl (which may have 1to 3 substituents selected from the substituent group B) or (b) a 5- to8-membered aromatic heterocyclic group which may have at least one of 1to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom (said aromatic heterocyclic group optionally having 1 to 3substituents selected from the substituent group B); (11) a grouprepresented by the formula —X″″—L—(CH₂)_(n)—M, wherein X″″ represents abond or C₁₋₄alkylene which may have 1 to 3 substituents selected fromthe substituent group A, and L represents (a) a bond, (b) C₆₋₁₀arylwhich may have 1 to 3 substituents selected from the substituent groupB, (c) a 5- to 8-membered aromatic heterocyclic group containing atleast one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom (said aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup B), (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—, n is an integerof 0 to 3, M represents an amino group, guanidino group, sulfamoylgroup, carbamoyl group or hydroxyl group; or (12) (a) C₁₋₁₀alkyl whichmay have 1 to 3 substituents selected from the substituent group C, (b)C₃₋₈cycloalkyl which may have 1 to 3 substituents selected from thesubstituent group C, (c) C₂₋₁₀alkenyl which may have 1 to 3 substituentsselected from the substituent group C, (d) C₃₋₈cycloalkenyl which mayhave 1 to 3 substituents selected from the substituent group C, (e)C₂₋₁₀alkynyl which may have 1 to 3 substituents selected from thesubstituent group C, (f) C₆₋₁₄aryl which may have 1 to 3 substituentsselected from the substituent group C, (g) C₆₋₁₄aryl-C₁₋₆alkyl which mayhave 1 to 3 substituents selected from the substituent group C, (h)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group C, (i) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group C, (j) a 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom,which may have 1 to 3 substituents selected from the substituent groupC, (k) acyl selected from formyl, C₁₋₁₀alkyl-carbonyl,C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup C), or (1) amino which may have 1 to 2 substituents selected fromacyl groups wherein a 5- to 8-membered aromatic heterocyclic group orsaturated or unsaturated non-aromatic heterocyclic group containing aleast one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom has been bound to a carbonyl or sulfonylgroup (said acyl optionally having 1 to 3 substituents selected from thesubstituent group C), and

R³ represents (1) C₁₋₁₀alkyl which may have 1 to 3 substituents selectedthe substituent group A; (2) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group A; (3) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupA; (4) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group A; (5) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group A; (6) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group A; (7)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group A; (8) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group A; (9)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (10) a group represented by the formula—X′″—G—(CH₂)_(n)—J, wherein X′″ represents C₁₋₄alkylene orC₂₋₄alkenylene, G represents a bond, —O—, —S—, —CO—NH— or —NH—CO—, n isan integer of 0 to 3, and J represents (a) a C₆₋₁₄aryl group (which mayhave 1 to 3 substituents selected from the substituent group B) or (b) a5- to 8-membered aromatic heterocyclic group which may have at least oneof 1 to 3 kinds of heteroatoms selected from oxygen atom, sulfur atomand nitrogen atom (said aromatic heterocyclic group optionally having 1to 3 substituents selected from the substituent group B); or (11) agroup represented by the formula —X″″—L—(CH₂)_(n)—M, wherein X″″represents a bond or C₁₋₄alkylene which may have 1 to 3 substituentsselected from the substituent group A, and L represents (a) a bond, (b)C₆₋₁₀aryl (which may have 1 to 3 substituents selected from thesubstituent group B), or (c) a 5- to 8-membered aromatic heterocyclicgroup containing at least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom (said aromaticheterocyclic group optionally having 1 to 3 substituents selected fromthe substituent group B), (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—,n is an integer of 0 to 3, M represents amino group, guanidino group,sulfamoyl group, carbamoyl group or hydroxyl group;

5) The compound according to the above 2), wherein R¹ is (1) hydrogenatom; (2) C₁₋₁₀alkyl which may have 1 to 3 substituents selected from(1′) halogen atom, (2′) nitro, (3′) cyano, (4′) oxo, (5′) hydroxylgroup, (6′) thiol, (7′) C₁₋₄alkylthio, (8′) amino group, (9′)mono-C₁₋₄alkylamino, (10′) di-C₁₋₄alkylamino, (11′) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, 2-oxo-1-pyrrolidinyl and2-oxo-1-piperidinyl, (12′) phenyl-C₁₋₄alkyl, (13′) C₃₋₇cycloalkyl, (14′)carboxyl, (15′) C₁₋₄alkoxy-carbonyl, (16′) C₇₋₁₀aralkyloxy-carbonyl,(17′) carbamoyl, (18′) mono-C₁₋₄alkylcarbamoyl, (19′)di-C₁₋₄alkylcarbamoyl, (20′) C₁₋₄alkyl which may be substituted with ahalogen atom or C₁₋₄alkoxy, (21′) C₁₋₄alkoxy which may be substitutedwith a halogen atom or C₁₋₄alkoxy, (22′) C₁₋₄alkylenedioxy, (23′)formyl, (24′) C₂₋₄alkanoyl, (25′) C₁₋₄alkylsulfonyl, (26′)C₁₋₄alkylsulfinyl, (27′) sulfamoyl, (28′) mono-C₁₋₄alkylsulfamoyl, (29′)di-C₁₋₄alkylsulfamoyl, (30′) C₆₋₁₄aryl (which may be substituted with asubstituent(s) selected from (1″) halogen, (2″) nitro, (3″) cyano, (4″)hydroxyl group, (5″) thiol, (6″) C₁₋₄alkylthio, (7″) amino, (8″)mono-C₁₋₄alkylamino, (9″) di-C₁₋₄alkylamino, (10″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (11″)phenyl-C₁₋₄alkyl, (12″) C₃₋₇cycloalkyl, (13″) carboxyl group, (14″)C₁₋₄alkoxy-carbonyl, (15″) C₇₋₁₀aralkyloxy-carbonyl, (16″) carbamoyl,(17″) mono-C₁₋₄alkyl-carbamoyl, (18″) di-C₁₋₄alkyl-carbamoyl, (19″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(20″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (21″) C₁₋₄alkylenedioxy, (22′) formyl, (23″) C₂₋₄alkanoyl,(24″) C₁₋₄alkylsulfonyl, (25″) C₁₋₄alkylsulfinyl, (26″) sulfamoyl, (27″)mono-C₁₋₄alkylsulfamoyl, (28″) di-C₁₋₄alkylsulfamoyl, and (29′) 5- to6-membered aromatic monocyclic heterocyclic group), or (31′) 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom(said heterocyclic group may have 1 to 3 substituents selected from (1″)halogen, (2″) nitro, (3″) cyano, (4″) oxo, (5″) hydroxyl group, (6″)thiol, (7″) C₁₋₄alkylthio, (8″) amino, (9″) mono-C₁₋₄alkylamino, (10″)di-C₁₋₄alkylamino, (11″) 5- to 6-membered cyclic amino selected fromtetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole and imidazole, (12″) phenyl-C₁₋₄alkyl, (14″) C₃₋₇cycloalkyl,(15″) carboxyl, (16″) C₁₋₄alkoxy-carbonyl, (17″)C₇₋₁₀aralkyloxy-carbonyl, (18″) carbamoyl, (19″)mono-C₁₋₄alkyl-carbamoyl, (20″) di-C₁₋₄alkyl-carbamoyl, (21″) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (22″)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(23″) C₁₋₄alkylenedioxy, (24″) formyl, (25″) C₂₋₄alkanoyl, (26″)C₁₋₄alkylsulfonyl and (27″) C₁₋₄alkylsulfinyl) (hereinafter referred toas substituent group D); (3) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group D; (4) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupD; (5) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group D; (6) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group D; (7) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group D; (8)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group D; (9) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group D; (10)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group D; (11) a group represented by the formula—X′″—G—(CH₂)_(n)—J, wherein X′″ represents C₁₋₄alkylene orC₂₋₄alkenylene, G is a bond, —O—, —S—, —CO—NH— or —NH—CO—, n is aninteger of 0 to 3, J represents (a) C₆₋₁₄aryl (which may have 1 to 3substituents selected from (1″) halogen, (2″) nitro, (3″) cyano, (4″)hydroxyl group, (5″) thiol, (6″) C₁₋₄alkylthio, (7″) amino, (8″)mono-C₁₋₄alkylamino, (9″) di-C₁₋₄alkylamino, (10″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, 2-oxo-1-pyrrolidinyl and2-oxo-1-piperidinyl, (11″) phenyl-C₁₋₄alkyl, (12″) C₃₋₇cycloalkyl, (13″)carboxyl, (14″) C₁₋₄alkoxy-carbonyl, (15″) C₇₋₁₀aralkyloxy-carbonyl,(16″) carbamoyl, (17″) mono-C₁₋₄alkyl-carbamoyl, (18″)di-C₁₋₄alkyl-carbamoyl, (19″) C₁₋₄alkyl which may be substituted with ahalogen atom or C₁₋₄alkoxy, (20″) C₁₋₄alkoxy which may be substitutedwith a halogen atom or C₁₋₄-alkoxy, (21″) C₁₋₄alkylenedioxy, (22″)formyl, (23″) C₂₋₄alkanoyl, (24″) C₁₋₄alkylsulfonyl, (25″)C₁₋₄alkylsulfinyl, (26″) sulfamoyl, (27″) mono-C₁₋₄alkylsulfamoyl, (28″)di-C₁₋₄alkylsulfamoyl, (29″) C₆₋₁₄aryl (which may be substituted with asubstituent selected from (1′″) halogen, (2′″) nitro, (3′″) cyano, (4′″)hydroxyl group, (5′″) thiol, (6′″) C₁₋₄alkylthio, (7′″) amino, (8′″)mono-C₁₋₄alkylamino, (9′″) di-C₁₋₄alkylamino, (10′″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (11′″)phenyl-C₁₋₄alkyl, (12′″) C₃₋₇cycloalkyl, (13′″) carboxyl group, (14′″)C₁₋₄alkoxy-carbonyl, (15′″) C₇₋₁₀aralkyloxy-carbonyl, (16′″) carbamoyl,(17′″) mono-C₁₋₄alkyl-carbamoyl, (18′″) di-C₁₋₄alkyl-carbamoyl, (19′″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(20′″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (21′″) C₁₋₄alkylenedioxy, (22′″) formyl, (23′″)C₂₋₄alkanoyl, (24′″) C₁₋₄alkylsulfonyl, (25′″) C₁₋₄alkylsulfinyl, (26′″)sulfamoyl, (27′″) mono-C₁₋₄alkylsulfamoyl, (28′″) di-C₁₋₄alkylsulfamoyland (29′″) 5- to 6-membered aromatic monocyclic heterocyclic group, or(30″) 5- to 8-membered aromatic heterocyclic group or saturated orunsaturated non-aromatic heterocyclic group containing at least one of 1to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom (said heterocyclic group may have 1 to 3 substituentsselected from (1′″) halogen, (2′″) nitro, (3′″) cyano, (4′″) oxo, (5′″)hydroxyl group, (6′″) thiol, (7′″) C₁₋₄alkylthio, (8′″) amino, (9′″)mono-C₁₋₄alkylamino, (10′″) di-C₁₋₄alkylamino, (11′″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (12′″)phenyl-C₁₋₄alkyl, (13′″) C₃₋₇cycloalkyl, (14′″) carboxyl, (15′″)C₁₋₄alkoxy-carbonyl, (16′″) C₇₋₁₀aralkyloxy-carbonyl, (17′″) carbamoyl,(18′″) mono-C₁₋₄alkyl-carbamoyl, (19′″) di-C₁₋₄alkyl-carbamoyl, (20′″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(21′″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (22′″) C₁₋₄alkylenedioxy, (23′″) formyl, (24′″)C₂₋₄alkanoyl, (25′″) C₁₋₄alkylsulfonyl and (26′″) C₁₋₄alkylsulfinyl)(hereinafter referred to as substituent group E), or (b) a 5- to8-membered heterocyclic group containing at least one of 1 to 3 kinds ofheterocyclic groups selected from oxygen atom, sulfur atom and nitrogenatom, said aromatic heterocyclic group optionally having 1 to 3substituents selected from the substituent group E; or (12) a grouprepresented by the formula —X″″—L—(CH₂)_(n)—M, wherein X″″ represents abond or a C₁₋₄alkylene group which may have 1 to 3 substituents selectedfrom the substituent group D, L represents (a) a bond, (b) C₆₋₁₀arylwhich may have 1 to 3 substituents selected from the substituent groupE, (c) a 5- to 8-membered aromatic heterocyclic group containing atleast one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom (said aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup E), (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—, n is an integerof 0 to 3, and M represents an amino group, guanidino group, sulfamoylgroup, carbamoyl group or hydroxyl group,

X represents the following saturated divalent groups wherein some bondsmay have been converted into unsaturated bonds:

(1) —(CH₂)_(f1)—, wherein f1 represents an integer of 1 to 8,

(2) —(CH₂)_(g1)—X¹—(CH₂)_(g2)—, wherein g1 and g2 are the same ordifferent, and represent an integer of 0 to 7, provided that the sum ofg1 and g2 is 0 to 7, and X¹ represents NH, O, S, SO or SO₂, or

(3) —(CH₂)_(h1)—X¹—(CH₂)_(h2)—X²—(CH₂)_(h3)—, wherein h1, h2 and h3 arethe same or different, and represent an integer of 0 to 6, provided thatthe sum of h1, h2 and h3 is 0 to 6, and X¹ and X² each represent NH, O,S, SO or SO₂ provided that when h2 is 0, X¹ and/or X² preferablyrepresent NH,

A represents (1) (a) C₁₋₁₀alkyl which may have 1 to 3 substituentsselected from (1″) halogen, (2″) nitro, (3″) cyano, (4″) oxo, (5″)hydroxyl group, (6″) thiol, (7″) C₁₋₄alkylthio, (8″) amino, (9″)mono-C₁₋₄alkylamino, (10″) di-C₁₋₄alkylamino, (11″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (12″)phenyl-C₁₋₄alkyl, (13″) C₃₋₇cycloalkyl, (14″) carboxyl, (15″)C₁₋₄alkoxy-carbonyl, (16″) C₇₋₁₀aralkyloxy-carbonyl, (17″) carbamoyl,(18″) mono-C₁₋₄alkyl-carbamoyl, (19″) di-C₁₋₄alkyl-carbamoyl, (20″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(21″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (22″) C₁₋₄alkylenedioxy, (23″) formyl, (24″) C₂₋₄alkanoyl,(25″) C₁₋₄alkylsulfonyl and (26″) C₁₋₄alkylsulfinyl (hereinafterreferred to as substituent group F), (b) C₃₋₈cycloalkyl which may have 1to 3 substituents selected from the substituent group F, (c)C₂₋₁₀alkenyl which may have 1 to 3 substituents selected from thesubstituent group F, (d) C₃₋₈cycloalkenyl which may have 1 to 3substituents selected from the substituent group F, (e) C₂₋₁₀alkynylwhich may have 1 to 3 substituents selected from the substituent groupF, (f) C₆₋₁₄aryl which may have 1 to 3 substituents selected from thesubstituent group F, (g) C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group F, (h)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group F, (i) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group F, (j) a 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom,which may have 1 to 3 substituents selected from the substituent groupF, (k) acyl selected from formyl, C₁₋₁₀alkyl-carbonyl,C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup F, or (l) amino which may have 1 to 2 substituents selected fromacyl wherein a 5- to 8-membered aromatic heterocyclic group or saturatedor unsaturated non-aromatic heterocyclic group containing a least one of1 to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom has been bound to carbonyl or sulfonyl (said acyloptionally having 1 to 3 substituents selected from the substituentgroup F); or (2) cyclic amino which may have 1 to 3 substituentsselected from (a) halogen, (b) nitro, (c) cyano, (d) hydroxyl group, (e)thiol, (f) amino, (g) carboxyl, (h) optionally halogenated C₁₋₄alkyl,(i) optionally halogenated C₁₋₄alkoxy, (j) formyl, (k) C₂₋₄alkanoyl and(1) C₁₋₄alkylsulfonyl; or (3) a group formed by removing one hydrogenatom from a 5- to 8-membered aromatic monocyclic heterocyclic ring orsaturated or unsaturated non-aromatic monocyclic heterocyclic ringcontaining one nitrogen atom and one to three kinds of 1 to 4heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogenatom or by removing one hydrogen atom from a ring wherein 2 or 3 of thesame or different rings selected from the above monocyclic rings havebeen condensed (said heterocyclic group optionally having 1 to 3substituents selected from the substituent group F),

R² and R³ each represents (1) C₁₋₁₀alkyl which may have 1 to 3substituents selected from the substituent group D; (2) C₃₋₈cycloalkylwhich may have 1 to 3 substituents selected from the substituent groupD; (3) C₂₋₁₀alkenyl which may have 1 to 3 substituents selected from thesubstituent group D; (4) C₃₋₈cycloalkenyl which may have 1 to 3substituents selected from the substituent group D; (5) C₂₋₁₀alkynylwhich may have 1 to 3 substituents selected from the substituent groupD; (6) C₆₋₁₄aryl which may have 1 to 3 substituents selected from thesubstituent group D; (7) C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group D; (8) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group D; (9) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group D; (10) a grouprepresented by the formula —X′″—(CH₂)_(n)—J, wherein X′″ representsC₁₋₄alkylene or C₂₋₄alkenylene, G represents a bond, —O—, —S—, —CO—NH—or —NH—CO—, n is an integer of 0 to 3, and J represents (a) C₆₋₁₄arylwhich may have 1 to 3 substituents selected from the substituent group Eor (b) a 5- to 8-membered aromatic heterocyclic group which may have atleast one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom (said aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup E), or (11) a group represented by the formula —X″″—L—(CH₂)_(n)—M,wherein X″″ represents a bond or C₁₋₄alkylene which may have 1 to 3substituents selected from the substituent group D, and L represents (a)a bond, (b) C₆₋₁₀aryl which may have 1 to 3 substituents selected fromthe substituent group E, (c) a 5- to 8-membered aromatic heterocyclicgroup containing at least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom (said aromaticheterocyclic group optionally having 1 to 3 substituents selected fromthe substituent group E), (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—,n is an integer of 0 to 3, M represents an amino group, guanidino group,sulfamoyl group, carbamoyl group or hydroxyl group;

6) A compound represented by the formula:

wherein each symbol is as defined in the above 2), or a salt thereof;

7) A compound represented by the formula:

wherein each symbol is as defined in the above 2), or a salt thereof;

8) A compound represented by the formula:

wherein each symbol is as defined in the above 2), or a salt thereof;

9) The compound according to the above 2), wherein the group representedby the formula:

is a group represented by the formula:

wherein R¹ represents (1) hydrogen atom, (2) C₁₋₁₀alkyl, (3)C₃₋₈cycloalkyl, (4) C₂₋₁₀alkenyl, (5) C₃₋₈cycloalkenyl, (6)C₂₋₁₀alkynyl, (7) C₆₋₁₄aryl, (8) C₆₋₁₄aryl-C₁₋₆alkyl, (9)di-C₆₋₁₄aryl-C₁₋₆alkyl, (10) tri-C₆₋₁₄aryl-C₁₋₆alkyl, (11) a grouprepresented by the formula —X′″—G—(CH₂)_(n)—J, wherein X′″ represents aC₁₋₄alkylene group or C₂₋₄alkenylene group, G represents a bond, —O—,—S—, —CO—NH— or —NH—CO—, n is an integer of 0 to 3, J represents (a)C₆₋₁₄aryl or (b) a 5- to 8-membered aromatic heterocyclic groupcontaining at least one of 1 to 3 kinds of heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom, or (12) a group representedby the formula —X″″—L—(CH₂)_(n)—M, wherein X″″ represents a bond or aC₁₋₄alkylene group, L represents (a) a bond, (b) C₆₋₁₀aryl, (c) a 5- to8-membered aromatic heterocyclic group containing at least one of 1 to 3kinds of heteroatoms selected from oxygen atom, sulfur atom and nitrogenatom, (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—, n is an integer of 0to 3, and M represents an amino group, guanidino group, sulfamoyl group,carbamoyl group or hydroxyl group, X′ represents C₁₋₆alkylene, R⁴ and R⁵each represents hydrogen atom or C₁₋₆alkyl (which may have 1 to 3substituents selected from (i) halogen, (ii) nitro, (iii) cyano, (iv)hydroxyl group, (v) thiol, (vi) C₁₋₄alkylthio, (vii) amino, (viii)mono-C₁₋₄alkylamino, (ix) di-C₁₋₄alkylamino, (x) 5- to 6-membered cyclicamino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (xi) carboxyl, (xii)C₁₋₄alkoxy-carbonyl, (xiii) C₇₋₁₀aralkyloxy-carbonyl, (xiv) carbamoyl,(xv) mono-C₁₋₄alkyl-carbamoyl, (xvi) di-C₁₋₄alkyl-carbamoyl, (xvii)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(xviii) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (xix) C₁₋₄alkylenedioxy, (xx) phenyl-C₁₋₄alkyl, (xxi)C₃₋₇cycloalkyl, (xxii) formyl, (xxiii) C₂₋₄alkanoyl, (xxiv)C₁₋₄alkylsulfonyl and (xxv) C₁₋₄alkylsulfinyl), and R⁴ and R⁵ togetherwith their adjacent nitrogen atom may be bound to each other to form a3- to 8-membered cyclic amino group;

10) The compound according to the above 9), wherein each of R⁴ and R⁵ ishydrogen atom;

11) The compound according to the above 9), wherein R⁴ and R⁵ are boundto each other to form a 3- to 8-membered saturated nitrogen-containingheterocyclic ring;

12) The compound according to the above 2), wherein the grouprepresented by the formula:

is a group represented by the formula:

wherein X″ represents a bond or C₁₋₄alkylene, and rings D and E eachrepresents a 3- to 8-membered saturated nitrogen-containing heterocyclicring;

13) The compound according to the above 2), wherein R² is a grouprepresented by the formula —X′″—G—(CH₂)_(n)—J wherein X′″ represents aC₁₋₄alkylene group or C₂₋₄alkenylene group, G represents a bond, —O—,—S—, —CO—NH— or —NH—CO—, n is an integer of 0 to 3, J represents (a) aC₆₋₁₄aryl group (which may have 1 to 3 substituents selected from (i)halogen, (ii) hydroxyl group, (iii) C₁₋₄alkyl which may be substitutedwith a halogen atom or C₁₋₄alkoxy, (iv) C₁₋₄alkoxy which may besubstituted with a halogen atom or C₁₋₄alkoxy and (v) sulfamoyl), or (b)a 5- to 8-membered aromatic heterocyclic group containing at least oneof 1 to 3 kinds of heteroatoms selected from oxygen atom, sulfur atomand nitrogen atom;

14) The compound according to the above 2), wherein R² is a grouprepresented by the formula —X″″—L—(CH₂)_(n)—M wherein X″″ represents abond or a C₁₋₄alkylene group, L represents (a) a bond, (b) C₆₋₁₄aryl,(c) a 5- to 8-membered aromatic heterocyclic group containing at leastone of 1 to 3 kinds of heteroatoms selected from oxygen atom, sulfuratom and nitrogen atom, (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—, nis an integer of 0 to 3, and M represents an amino group, guanidinogroup, sulfamoyl group, carbamoyl group or hydroxyl group;

15) The compound according to the above 2), wherein R³ represents agroup represented by the formula —(CH₂)_(p)—T, wherein p is an integerof 1 to 6, T represents (a) C₆₋₁₄aryl (which may have 1 to 3substituents selected from (i) halogen, (ii) hydroxyl group, (iii)phenyl-C₁₋₄alkyl, (iv) carboxyl, (v) C₁₋₄alkoxy-carbonyl, (vi) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (vii)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(viii) C₁₋₄alkylenedioxy, (ix) sulfamoyl, (x) C₁₋₄alkylsulfamoyl, (xi)di-C₁₋₄alkylsulfamoyl and (xii) a 5- to 8-membered aromatic heterocyclicgroup or saturated or unsaturated non-aromatic heterocyclic groupcontaining at least one of 1 to 3 kinds of heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom, or (b) a 5- to 8-memberedaromatic heterocyclic group containing at least one of 1 to 3 kinds ofheteroatoms selected from oxygen atom, sulfur atom and nitrogen atom;

16) The compound according to the above 14), wherein T is phenyl groupsubstituted with hydroxyl group, sulfamoyl, C₁₋₄alkylsulfamoyl ordi-C₁₋₄alkylsulfamoyl;

17)3′-{[{2-[4-(Aminosulfonyl)phenyl]ethyl}(4-phenylbutanoyl)amino]methyl}-N-[2-(1-pyrrolidinyl)ethyl]-[1,1′-biphenyl]-3-carboxamideor a salt thereof;

18)3′-({{2-[4-(Aminosulfonyl)phenyl]ethyl}-[(benzyloxy)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)-ethyl][1,1′-biphenyl]-3-carboxamideor a salt thereof;

19)N-(2-Aminoethyl)-3′-{[[3-({[amino(imino)methyl]-amino}methyl)benzoyl](1-naphthylmethyl)amino]methyl}-1,1′-biphenyl]-2-carboxamideor a salt thereof;

20)N-(2-Aminoethyl)-3′-{[[4-(aminosulfonyl)benzoyl]-(1-naphthylmethyl)amino]methyl}-1,1′-biphenyl-2-carboxamideor a salt thereof;

21) A prodrug of the compound according to the above 1) or 2) or a saltthereof;

22) A pharmaceutical composition comprising a compound represented bythe formula (I):

wherein R¹ represents hydrogen atom or an optionally substitutedhydrocarbon group; X represents a spacer whose linear chain moiety iscomposed of 1 to 12 atoms; R¹ and X may be bound to each other to form aring; A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group; R²represents an optionally substituted hydrocarbon group or an optionallysubstituted amino group; R³ represents an optionally substitutedhydrocarbon group; and rings B and C each represents a furtheroptionally substituted benzene ring, provided that (1) a compoundrepresented by the formula:

wherein each symbol has the same meaning as defined above, and (2)4′-[[(methoxyacetyl)methylamino]methyl]-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-[1,1′-biphenyl]-4-carboxamideare excluded, or a salt thereof or a prodrug thereof;

23) A GPR14 antagonist comprising a compound represented by the formula(I):

wherein R¹ represents hydrogen atom or an optionally substitutedhydrocarbon group; X represents a spacer whose linear chain moiety iscomposed of 1 to 12 atoms; R¹ and X may be bound to each other to form aring; A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group; R²represents an optionally substituted hydrocarbon group or an optionallysubstituted amino group; R³ represents an optionally substitutedhydrocarbon group; and rings B and C each represents a furtheroptionally substituted benzene ring, or a salt thereof or a prodrugthereof;

24) A vasoconstriction inhibitor comprising a compound represented bythe formula (I):

wherein R¹ represents hydrogen atom or an optionally substitutedhydrocarbon group; X represents a spacer whose linear chain moiety iscomposed of 1 to 12 atoms; R¹ and X may be bound to each other to form aring; A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group; R²represents an optionally substituted hydrocarbon group or an optionallysubstituted amino group; R³ represents an optionally substitutedhydrocarbon group; and rings B and C each represents a furtheroptionally substituted benzene ring, or a salt thereof or a prodrugthereof;

25) An agent for preventing and/or treating hypertension,arteriosclerosis, cardiac hypertrophy, myocardial infarction or heartfailure, comprising a compound represented by the formula (I):

wherein R¹ represents hydrogen atom or an optionally substitutedhydrocarbon group; X represents a spacer whose linear chain moiety iscomposed of 1 to 12 atoms; R¹ and X may be bound to each other to form aring; A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group; R²represents an optionally substituted hydrocarbon group or an optionallysubstituted amino group; R³ represents an optionally substitutedhydrocarbon group; and rings B and C each represents a furtheroptionally substituted benzene ring, or a salt thereof or a prodrugthereof;

26) A regulator for a somatostatin receptor function comprising acompound represented by the formula (I):

wherein R¹ represents hydrogen atom or an optionally substitutedhydrocarbon group; X represents a spacer whose linear chain moiety iscomposed of 1 to 12 atoms; R¹ and X may be bound to each other to form aring; A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group, R²represents an optionally substituted hydrocarbon group or an optionallysubstituted amino group; R³ represents an optionally substitutedhydrocarbon group; and rings B and C each represents a furtheroptionally substituted benzene ring, or a salt thereof or a prodrugthereof;

27) The regulator for a somatostatin receptor function according to theabove 26) which is a somatostatin receptor agonist;

28) The regulator for a somatostatin receptor function according to theabove 26) which is a somatostatin receptor antagonist;

29) The regulator for a somatostatin receptor function according to theabove 26), which is a somatostatin type 5 receptor function regulator;

30) The regulator for a somatostatin receptor function according to theabove 26), which is an agent for preventing and/or treating diabetes,obesity, diabetic complications, diseases in the central nervous system,diseases in the digestive organs, glaucoma, acromegaly or tumors;

31) A method of antagonizing GPR14, which comprises administering, intoa mammal, an effective amount of a compound represented by the formula(I):

wherein R¹ represents hydrogen atom or an optionally substitutedhydrocarbon group; X represents a spacer whose linear chain moiety iscomposed of 1 to 12 atoms; R¹ and X may be bound to each other to form aring; A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group; R²represents an optionally substituted hydrocarbon group or an optionallysubstituted amino group; R³ represents an optionally substitutedhydrocarbon group; and rings B and C each represents a furtheroptionally substituted benzene ring, or a salt thereof;

32) A method of regulating a somatostatin receptor function whichcomprises administering, into a mammal, an effective amount of acompound represented by the formula (I):

wherein R¹ represents hydrogen atom or an optionally substitutedhydrocarbon group; X represents a spacer whose linear chain moiety iscomposed of 1 to 12 atoms; R¹ and X may be bound to each other to form aring; A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group; R²represents an optionally substituted hydrocarbon group or an optionallysubstituted amino group; R³ represents an optionally substitutedhydrocarbon group; and rings B and C each represents a furtheroptionally substituted benzene ring, or a salt thereof;

33) Use of a compound represented by the formula (I):

wherein R¹ represents hydrogen atom or an optionally substitutedhydrocarbon group; X represents a spacer whose linear chain moiety iscomposed of 1 to 12 carbon atoms; R¹ and X may be bound to each other toform a ring; A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group; R²represents an optionally substituted hydrocarbon group or an optionallysubstituted amino group; R³ represents an optionally substitutedhydrocarbon group; and rings B and C each represents a furtheroptionally substituted benzene ring, or a salt thereof, for themanufacture of a GPR14 antagonist;

34) Use of a compound represented by the formula (I):

wherein R¹ represents hydrogen atom or an optionally substitutedhydrocarbon group; X represents a spacer whose linear chain moiety iscomposed of 1 to 12 carbon atoms; R¹ and X may be bound to each other toform a ring; A represents an optionally substituted amino group or anoptionally substituted nitrogen-containing heterocyclic group; R²represents an optionally substituted hydrocarbon group or an optionallysubstituted amino group; R³ represents an optionally substitutedhydrocarbon group; and rings B and C each represents a furtheroptionally substituted benzene ring, or a salt thereof, for themanufacture of a somatostatin receptor regulator;

35) A process for producing the compound according to the above 1) or asalt thereof, which comprises (i) reacting a compound represented by theformula:

wherein each symbol is as defined in the above 1), or a salt thereof,with a compound represented by the formula: R²COOH wherein R² is asdefined in the above 1), or a salt thereof, or a reactive derivativethereof, or

(ii) reacting a compound represented by formula:

wherein each symbol is as defined in the above 1), or a salt thereof ora reactive derivative thereof, with a compound represented by theformula:

wherein each symbol is as defined in the above 1), or a salt thereof;and the like.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

The term “GPR 14-antagonizing activity” used herein refers to anactivity to competitively or non-competitively inhibit the binding of aligand (e.g., urotensin II, etc.) to GPR14 protein on a cell membrane.

The present invention provides, based on such GPR 14-antagonizingactivity, drugs which exhibit a variety of effects on blood vessels(e.g., accentuation or suppression of vasoconstriction, etc.). Amongthem, vasoconstriction inhibitors may preferably be used which reduceurotensin II-induced potent vasoconstriction. The vasoconstrictioninhibitors can be used for preventing and/or treating a variety ofdiseases. Particularly, they may preferably be used for preventingand/or treating hypertension, arteriosclerosis, hypercardia, myocardialinfarction, heart failure and the like, and more preferably, ischemicmyocardial infarction, congestive heart failure and the like.

In the above-described formula (I), “a further optionally substitutedbenzene ring” represented by B or C is a benzene ring which may besubstituted in addition to the substituent shown in the formula (I) andexamples of the substituent (other than the substituent shown in theformula (I)) include hydrocarbon group which may be substituted;heterocyclic group which may be substituted; nitro group; a halogenatom; amino group which may be substituted; a group represented by theformula: R⁶—Y— (wherein Y is oxygen atom or sulfur atom which may beoxidized (e.g., S, S(O), S(O)₂, etc.) and R⁶ is a hydrocarbon groupwhich may be substituted or a heterocyclic group which may besubstituted); cyano group; acyl group which may be substituted; carboxylgroup which may be esterified or amidated; and the like.

Examples of the hydrocarbon group in the “hydrocarbon group which may besubstituted” as the substituent of the benzene ring of “a furtheroptionally substituted benzene ring” represented by B or C, and in the“hydrocarbon group which may be substituted” represented by R⁶ include

(1) alkyl (e.g., C₁₋₁₀alkyl such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,hexyl, heptyl, octyl, nonyl or decyl, etc., and preferably lower (C₁₋₆)alkyl, etc.);

(2) cycloalkyl (e.g., C₃₋₈cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc.), wherein the cycloalkyl maybe condensed with a benzene ring to form indan (e.g., indan 1-yl, indan2-yl, etc.), tetrahydronaphthalene (e.g., tetrahydronaphthalene-5-yl,tetrahydronaphthalene-6-yl, etc.) (preferably indan, etc.), and whereinthe cycloalkyl may be crosslinked with via a C₁₋₂ linear atomic chain toform a crosslinked cyclic hydrocarbon group such asbicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo [3.2.1]octyl,bicyclo[3.2.2]nonyl, etc. (preferably cyclohexyl having a crosslinkagevia a C₁₋₂ linear atomic chain, etc., and more preferablybicyclo[2.2.1]heptyl, etc.);(3) alkenyl (e.g., C₂₋₁₀alkenyl such as vinyl, allyl, crotyl, 2-pentenylor 3-hexenyl, etc., preferably lower (C₂₋₆) alkenyl);(4) cycloalkenyl (e.g., C₃₋₈cycloalkenyl such as 2-cyclopentenyl,2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);(5) alkynyl (e.g., C₂₋₁₀alkynyl such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-pentynyl, 3-hexynyl, etc., preferably lower (C₂₋₆) alkynyl,etc.);(6) aryl (e.g., C₆₋₁₄aryl such as phenyl or naphthyl, etc., preferablyC₆₋₁₀aryl, and more preferably phenyl, etc.);(7) aralkyl (e.g., C₁₋₆alkyl having 1 to 3 C₆₋₁₄allyl groups, preferablyphenyl-C₁₋₄alkyl (e.g., benzyl, phenethyl, etc.). Particularly, alkyl ispreferable, and C₁₋₄alkyl (e.g., methyl, ethyl, etc.) is more preferablewith methyl being most preferable.

The hydrocarbon group may have substituent(s). Examples of thesubstituent(s) include halogen (e.g., fluorine, chlorine, bromine,iodine, etc.), nitro, cyano, oxo, hydroxy group, thiol group which maybe substituted (e.g., thiol, C₁₋₄alkylthio, etc.), amino group which maybe substituted (e.g., amino, mono-C₁₋₄alkylamino, di-C₁₋₄alkylamino,mono-C₂₋₅alkanoylamino, or 5- or 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.), phenyl-lower (C₁₋₄) alkyl, C₃₋₇cycloalkyl,carboxyl group which may be esterified or amidated (e.g., carboxyl,C₁₋₄alkoxy-carbonyl, lower (C₇₋₁₀) aralkyloxy-carbonyl, carbamoyl,mono-C₁₋₄alkyl-carbamoyl, di-C₁₋₄alkyl-carbamoyl, etc.), C₁₋₄alkyl whichmay be substituted by halogen atom or C₁₋₄alkoxy (e.g., trifluoromethyl,methyl, ethyl, etc.), C₁₋₄alkoxy which may be substituted by halogenatom or C₁₋₄alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄alkylenedioxy (e.g., —O—CH₂—O—,—O—CH₂—CH₂—O—, etc.), formyl, C₂₋₄alkanoyl (e.g., acetyl, propionyl,etc.), C₁₋₄alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.),C₁₋₄alkylsulfinyl (e.g., methanesulfinyl, ethanesulfinyl, etc.), etc.The number of the substituents is preferably 1 to 3.

Examples of the heterocyclic group in the “heterocyclic group which maybe substituted” as the substituent of the benzene ring of “a furtheroptionally substituted benzene ring” represented by B or C, and in the“heterocyclic group which may be substituted” represented by R⁶ includethose which may be formed by removing one hydrogen atom from a 5- to8-membered aromatic heterocyclic ring and saturated or unsaturatednon-aromatic (aliphatic) heterocyclic ring containing at least 1(preferably 1 to 4, and more preferably 1 or 2) of 1 to 3 (preferably 1or 2) kinds of heteroatom(s) selected from the group consisting ofoxygen, sulfur and nitrogen atoms.

Examples of the “aromatic heterocyclic ring” include 5- to 8-membered(preferably 5- or 6-membered) aromatic monocyclic heterocyclic rings(e.g., furan, thiophene, pyrrole, oxazole, isoxazole, thiazole,isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,3,4-thiadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine or triazine, etc.). Examples of the“non-aromatic heterocyclic ring” include 5- to 8-membered (preferably 5-or 6-membered) saturated or unsaturated monocyclic non-aromaticheterocyclic ring (aliphatic heterocyclic ring) such as pyrrolidine,tetrahydrofuran, tetrahydrothiophene, thiolane, dithiolane, oxathiolane,pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline,oxazine, oxadiazine, thiazine, thiadiazine, piperidine, morpholine,thiomorpholine, tetrahydropyran, piperazine, pyran, oxepine, thiepine,azepine, etc.; and 5- to 8-membered non-aromatic heterocyclic ringscomprising any of the above-described aromatic monocyclic heterocyclicrings with all or a portion of double bonds therein being saturated.

Examples of the “heterocyclic group” in the “heterocyclic group whichmay be substituted” as the substituent of the benzene ring of “a furtheroptionally substituted benzene ring” represented by B or C, and in“heterocyclic group which may be substituted” represented by R⁶ alsoinclude those formed by removing one hydrogen atom from a condensed ringformed by condensation of two or three (preferably two) rings selectedfrom the group consisting of the above-listed monocyclic heterocyclicrings (monocyclic aromatic heterocyclic rings and monocyclicnon-aromatic heterocyclic rings) and 5- to 8-membered cyclichydrocarbons (e.g., 5- to 8-membered (preferably 5- or 6-membered)saturated or unsaturated alicyclic hydrocarbons such as C₅₋₈cycloalkane,C₅₋₈cycloalkene, C₅₋₈cycloalkadiene, etc., and 6-membered aromatichydrocarbon such as benzene. Those condensed rings may be saturated,partially unsaturated or aromatic.

Preferable examples of such condensed ring include those comprising twoidentical or different heterocyclic rings (preferably one is aheterocyclic ring and the other an aromatic heterocyclic ring, and morepreferably two identical or different aromatic heterocyclic rings), andthose comprising one heterocyclic ring and one homocyclic ring(preferably one is a heterocyclic ring and the other a benzene ring, andmore preferably one is an aromatic heterocyclic ring and the other abenzene ring). Specific examples of such condensed ring include indole,benzothiophene, benzofuran, benzimidazole, imidazo[1,2-a]pyridine,quinoline, isoquinoline, cinnoline, etc.

The “heterocyclic group” in the “heterocyclic group which may besubstituted” as the substituent of the benzene ring of “a furtheroptionally substituted benzene ring” represented by B or C, and in“heterocyclic group which may be substituted” represented by R⁶ may havesubstituent(s). Examples thereof include those similar to theabove-listed substituents of the “hydrocarbon group which may besubstituted” as the substituent of the benzene ring of “a furtheroptionally substituted benzene ring” represented by B or C.

Examples of the “halogen atom” as the substituent of benzene ring of “afurther optionally substituted benzene ring” represented by B or Cinclude fluorine, chlorine, bromine and iodine.

Examples of the “amino group which may be substituted” as thesubstituent of the benzene ring of “a further optionally substitutedbenzene ring” represented by B or C include that similar to the “aminogroup which may be substituted” represented by A described hereinafter.Among them, preferred are amino group having one or two substituentsselected from the group consisting of “hydrocarbon group which may besubstituted” (those similar to the above-listed “hydrocarbon group whichmay be substituted” as the substituent of the benzene ring of “a furtheroptionally substituted benzene ring” represented by B or C);“heterocyclic group which may be substituted” (those similar to theabove-listed “heterocyclic group which may be substituted” as thesubstituent of the benzene ring of “a further optionally substitutedbenzene ring” represented by B or C); and “acyl group which may besubstituted” (those similar to the “acyl group which may be substituted”as the substituent of the benzene ring of “a further optionallysubstituted benzene ring” represented by B or C). Particularly preferredare amino group which may have one or two alkyl groups which may besubstituted [e.g., C₁₋₁₀alkyl such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C₁₋₆) alkyl,which may have 1 to 3 substituent(s) selected from the group consistingof halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro,cyano, hydroxy group, thiol group which may be substituted (e.g., thiolor C₁₋₄alkylthio), amino group which may be substituted (e.g., amino,mono-C₁₋₄alkylamino, di-C₁₋₄alkylamino, 5- or 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc.), phenyl lower (C₁₋₄) alkyl,C₃₋₇cycloalkyl, carboxyl group which may be esterified or amidated(e.g., carboxyl, C₁₋₄alkoxycarbonyl, lower (C₇₋₁₀) aralkyloxy-carbonyl,carbamoyl, mono-C₁₋₄alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.),C₁₋₄alkyl which may be substituted by halogen atom or C₁₋₄alkoxy (e.g.,trifluoromethyl, methyl, ethyl, etc.), C₁₋₄alkoxy which may besubstituted by halogen atom or C₁₋₄alkoxy (e.g., methoxy, ethoxy,trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄alkylenedioxy (e.g.,—O—CH₂—O—, —O—CH₂—CH₂—O—, etc.), formyl, C₂₋₄alkanoyl (e.g., acetyl,propionyl, etc.), C₁₋₄alkylsulfonyl (e.g., methanesulfonyl,ethanesulfonyl, etc.), C₁₋₄alkylsulfinyl (e.g., methanesulfinyl,ethanesulfinyl, etc.), and the like].

The “amino group which may be substituted” as the substituent of thebenzene ring of “a further optionally substituted benzene ring”represented by B or C may also be an amino group in which thesubstituents of the amino group are bonded to each other to form acyclic amino group (e.g., a cyclic amino group formed by removing onehydrogen atom from constituent nitrogen atom of a 5- or 6-membered ringwith a bond on its nitrogen atom (e.g., tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.). Thecyclic amino group may be substituted and examples thereof includehalogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, thiol group, amino group, carboxyl group, C₁₋₄alkyl whichmay be halogenated (e.g., trifluoromethyl, methyl, ethyl, etc.),C₁₋₄alkoxy which may be halogenated (e.g., methoxy, ethoxy, propoxy,butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C₂₋₄alkanoyl(e.g., acetyl, propionyl, etc.) or C₁₋₄alkylsulfonyl (e.g.,methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of thesubstituents is preferably 1 to 3.

Examples of the “acyl group which may be substituted” as the substituentof the benzene ring of “a further optionally substituted benzene ring”represented by B or C include that comprising carbonyl group or sulfonylgroup bonded with, for example: hydrogen; “hydrocarbon group which maybe substituted” (e.g., that similar to the above-listed “hydrocarbongroup which may be substituted” as the substituent of the benzene ringof “a further optionally substituted benzene ring” represented by B orC); or “heterocyclic group which may be substituted” (e.g., that similarto the above-listed “heterocyclic group which may be substituted” as thesubstituent of the benzene ring of “a further optionally substitutedbenzene ring” represented by B or C), and the like. Preferred examplesare those comprising carbonyl group or sulfonyl group bonded with, forexample:

(1) hydrogen;

(2) alkyl which may be substituted (e.g., C₁₋₁₀alkyl such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.,preferably lower (C₁₋₆) alkyl);

(3) cycloalkyl which may be substituted (e.g., C₃₋₇cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, etc.);

(4) alkenyl which may be substituted (e.g., C₂₋₁₀alkenyl such as allyl,crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C₂₋₆) alkenyl);

(5) cycloalkenyl which may be substituted (e.g., C₃₋₇cycloalkenyl suchas 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,2-cyclohexenylmethyl, etc.); and

(6) 5- or 6-membered monocyclic aromatic group which may be substituted(e.g., phenyl, pyridyl, etc.), including acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,octanoyl, cyclobutane carbonyl, cyclopentane carbonyl, cyclohexanecarbonyl, cycloheptane carbonyl, crotonyl, 2-cyclohexene carbonyl,benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl, etc.Examples of the substituent(s) of the above-described (2) alkyl whichmay be substituted, (3) cycloalkyl which may be substituted, (4) alkenylwhich may be substituted, (5) cycloalkenyl which may be substituted, and(6) 5- or 6-membered monocyclic aromatic group which may be substitutedinclude halogen (e.g., fluorine, chlorine, bromine or iodine); nitro;cyano; hydroxy group; thiol group which may be substituted (e.g., thiol,C₁₋₄alkylthio, etc.); amino group which may be substituted (e.g., amino,mono-C₁₋₄alkylamino, di-C₁₋₄alkylamino, 5- or 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc.); carboxyl group which may beesterified or amidated (e.g., carboxyl, C₁₋₄alkoxy-carbonyl, carbamoyl,mono-C₁₋₄alkyl-carbamoyl, di-C₁₋₄alkyl-carbamoyl, etc.); C₁₋₄alkyl whichmay be substituted by halogen atom or C₁₋₄alkoxy (e.g., trifluoromethyl,methyl, ethyl, etc.); C₁₋₄alkoxy which may be substituted by halogenatom or C₁₋₄alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy, etc.); formyl; C₂₋₄alkanoyl (e.g., acetyl, propionyl,etc.); C₁₋₄alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.);and C₁₋₄alkylsulfinyl (e.g., methanesulfinyl, ethanesulfinyl, etc.),etc. The number of the substituent(s) is preferably 1 to 3.

Examples of the “carboxyl group which may be esterified” as thesubstituent of the benzene ring of “a further optionally substitutedbenzene ring” represented by B or C include that comprising a carbonylgroup bonded with, for example, hydrogen atom, “hydrocarbon group whichmay be substituted” (e.g., that similar to the above-listed “hydrocarbongroup which may be substituted” as the substituent of the benzene ringof “a further optionally substituted benzene ring” represented by B orC) and preferred examples include:

(1) hydrogen;

(2) alkyl which may be substituted (e.g., C₁₋₁₀alkyl such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.,preferably lower (C₁₋₆) alkyl);

(3) cycloalkyl which may be substituted (e.g., C₃₋₇cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, etc.);

(4) alkenyl which may be substituted (e.g., C₂₋₁₀alkenyl such as allyl,crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C₂₋₆) alkenyl);

(5) cycloalkenyl which may be substituted (e.g., C₃₋₇cycloalkenyl suchas 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,2-cyclohexenylmethyl, etc.); and

(6) aryl which may be substituted (e.g., phenyl, naphthyl, etc.); morepreferably, carboxyl, lower (C₁₋₆) alkoxy-carbonyl, aryloxycarbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl,phenyoxycarbonyl, naphthoxycarbonyl) and the like. Examples of thesubstituent(s) of the above-described (2) alkyl which may besubstituted, (3) cycloalkyl which may be substituted, (4) alkenyl whichmay be substituted, (5) cycloalkenyl which may be substituted, and (6)aryl which may be substituted include halogen (e.g., fluorine, chlorine,bromine or iodine); nitro; cyano; hydroxy group; thiol group which maybe substituted (e.g., thiol, C₁₋₄alkylthio, etc.); amino group which maybe substituted (e.g., amino, mono-C₁₋₄alkylamino, di-C₁₋₄alkylamino, 5-or 6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.);carboxyl group which may be esterified or amidated (e.g., carboxyl,C₁₋₄alkoxy-carbonyl, carbamoyl, mono-C₁₋₄alkyl-carbamoyl,di-C₁₋₄alkyl-carbamoyl, etc.); C₁₋₄alkyl which may be substituted byhalogen atom or C₁₋₄alkoxy (e.g., trifluoromethyl, methyl, ethyl, etc.);C₁₋₄alkoxy which may be substituted by halogen atom or C₁₋₄alkoxy (e.g.,methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.); formyl;C₂₋₄alkanoyl (e.g., acetyl, propionyl, etc.); C₁₋₄alkylsulfonyl (e.g.,methanesulfonyl, ethanesulfonyl, etc.); and C₁₋₄alkylsulfinyl (e.g.,methanesulfinyl, ethanesulfinyl, etc.), etc. The number of thesubstituent(s) is preferably 1 to 3.

Examples of the “carboxyl group which may be amidated” as thesubstituent of the benzene ring of “a further optionally substitutedbenzene ring” represented by B or C include that comprising a carbonylgroup bonded with, for example:

(1) hydroxy group; or

(2) “amino group which may be substituted” (e.g., that similar to theabove-listed “amino group which may be substituted” as the substituentof the benzene ring of “a further optionally substituted benzene ring”represented by B or C), and the like.

The benzene ring of “a further optionally substituted benzene ring”represented by B or C may have 1 to 4 the same or differentsubstituent(s) (preferably 1 or 2 substituent(s)) at any position(s) ofthe ring. When the benzene ring of “a further optionally substitutedbenzene ring” represented by B or C have two or more substituents, anytwo of the substituents may be bonded to each other to form, forexample, lower (C₁₋₆) alkylene (e.g., trimethylene, tetramethylene,etc.), lower (C₁₋₆) alkyleneoxy (e.g., —CH₂—O—CH₂—, —O—CH₂—CH₂—, etc.),lower (C₁₋₆) alkylenedioxy (e.g., —O—CH₂—O—, —O—CH₂—CH₂—O—, etc.), lower(C₂₋₆) alkenylene (e.g., —CH₂—CH═CH—, —CH₂—CH₂—CH═CH—, —CH₂—CH═CH—CH₂—,etc.), lower (C₄₋₆) alkadienylene (e.g., —CH═CH—CH═CH—, etc.).

Preferred examples of the substituent of the benzene ring of “a furtheroptionally substituted benzene ring” represented by B or C include:hydrocarbon group which may be substituted; heterocyclic group which maybe substituted; nitro group; halogen atom; amino group which may besubstituted; and a group represented by the formula: R⁶—Y— (wherein Y isoxygen atom or sulfur atom which may be oxidized and R⁶ is a hydrocarbongroup which may be substituted or heterocyclic group which may besubstituted). More preferable are hydrocarbon group which may besubstituted, heterocyclic group which may be substituted, halogen atom,amino group which may be substituted and a group represented by theformula R⁶—Y— (wherein Y is oxygen atom or sulfur atom which may beoxidized and R⁶ is a hydrocarbon group which may be substituted orheterocyclic group which may be substituted), etc. Most preferable arelower (C₁₋₄) alkyl and halogen atom, etc.

Preferably, the “further optionally substituted benzene rings”represented by B or C are benzene rings which do not have anysubstituent other than that shown in the formula, respectively.

In the above-described formula (I), examples of the hydrocarbon group inthe “hydrocarbon group which may be substituted” represented by R¹, R²and R³ include

(1) alkyl (e.g., C₁₋₁₀alkyl such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,hexyl, heptyl, octyl, nonyl or decyl, etc., and preferably lower (C₁₋₆)alkyl, etc.);

(2) cycloalkyl (e.g., C₃₋₈cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc.), wherein the cycloalkyl maybe condensed with a benzene ring to form indan (e.g., indan 1-yl, indan2-yl, etc.), tetrahydronaphthalene (e.g., tetrahydronaphthalene-5-yl,tetrahydronaphthalene-6-yl, etc.) (preferably indan, etc.), and whereinthe cycloalkyl may be crosslinked with via a C₁₋₂ linear atomic chain toform a closslinked cyclic hydrocarbon group such asbicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[3.2.2]nonyl, etc. (preferably cyclohexyl having a crosslinkagevia a C₁₋₂ linear atomic chain, etc., and more preferablybicyclo[2.2.1]heptyl, etc.);(3) alkenyl (e.g., C₂₋₁₀alkenyl such as vinyl, allyl, crotyl, 2-pentenylor 3-hexenyl, etc., preferably lower (C₂₋₆) alkenyl);(4) cycloalkenyl (e.g., C₃₋₈cycloalkenyl such as 2-cyclopentenyl,2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);(5) alkynyl (e.g., C₂₋₁₀alkynyl such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-pentynyl, 3-hexynyl, etc., preferably lower (C₂₋₆) alkynyl,etc.);(6) aryl (e.g., C₆₋₁₄aryl such as phenyl or naphthyl, etc., preferablyC₆₋₁₀aryl, and more preferably phenyl, etc.);(7) aralkyl (e.g., C₁₋₆alkyl having 1 to 3 C₆₋₁₄allyl groups, preferablyphenyl-C₁₋₄alkyl (e.g., benzyl, phenethyl, etc.);(8) a group represented by the formula: —X′″—G—(CH₂)_(n)—J, wherein X′″represents a C₁₋₄alkylene group or a C₂₋₄alkenylene group, G representsa bond, —O—, —S—, —CO—NH— or —NH—CO—, n represents an integer of 0 to 3,and J represents an aromatic ring group which may be substituted; or(9) a group represented by the formula: —X″″—L—(CH₂)_(n)—M, wherein X″″represents a bond or a C₁₋₄alkylene group, L represents (a) a bond, (b)an aromatic ring group which may be substituted, (c) —O—, (d) —S—, (e)—CO—NH— or (f) —NH—CO—, n represents an integer of 0 to 3, M representsamino group, guanidino group, sulfamoyl group, carbamoyl group orhydroxyl group; and the like.

In the above-described formula, examples of the aromatic ring grouprepresented by J and L include an aryl group which may be substituted,an aromatic heterocyclic group which may be substituted, and the like.

Preferably, examples of the “aryl” of the “aryl group which may besubstituted” represented by J and L include C₆₋₁₄aryl such as phenyl,naphthyl, etc., more preferably phenyl, etc.

Examples of the “aromatic heterocyclic group” of the “aromaticheterocyclic group which may be substituted represented by J and Linclude those similar to “an aromatic heterocyclic group which may besubstituted” of the “heterocyclic group which may be substituted”exemplified with respect to R⁶ and, among them, a 5- or 6-memberedaromatic monocyclic heterocyclic ring is preferred. Examples of the 5-or 6-membered aromatic monocyclic heterocyclic ring include furan,thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadizaole,1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, triazine, etc.

The “aromatic ring group” of the “aromatic ring group which may besubstituted represented by J and L may have substituent(s). Examples ofsuch substituent include halogen (e.g., fluorine, chlorine, bromine,iodine, etc.), nitro, cyano, hydroxy group, thiol group which may besubstituted (e.g., thiol, C₁₋₄alkylthio, etc.), amino group which may besubstituted (e.g., amino, mono-C₁₋₄alkylamino, di-C₁₋₄alkylamino, or 5-or 6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole,2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl, etc.), phenyl-lower (C₁₋₄)alkyl, C₃₋₇cycloalkyl, carboxyl group which may be esterified oramidated (e.g., carboxyl, C₁₋₄alkoxy-carbonyl, lower (C₇₋₁₀)aralkyloxy-carbonyl, carbamoyl, mono-C₁₋₄alkyl-carbamoyl,di-C₁₋₄alkyl-carbamoyl, etc.), C₁₋₄alkyl which may be substituted byhalogen atom or C₁₋₄alkoxy (e.g., trifluoromethyl, methyl, ethyl, etc.),C₁₋₄alkoxy which may be substituted by halogen atom or C₁₋₄alkoxy (e.g.,methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.),C₁₋₄alkylenedioxy (e.g., —O—CH₂—O—, —O—CH₂—CH₂—O—, etc.), formyl,C₂₋₄alkanoyl (e.g., acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (e.g.,methanesulfonyl, ethanesulfonyl, etc.), C₁₋₄alkylsulfinyl (e.g.,methanesulfinyl, ethanesulfinyl, etc.), sulfamoyl which may besubstituted (e.g., sulfamoyl, mono-C₁₋₄alkylsulfamoyl,di-C₁₋₄alkylsulfamoyl, etc), an aryl group which may be substituted, aheterocyclic group which may be substituted, and the like. The number ofthe substituents is preferably 1 to 3.

The “hydrocarbon group” of the “hydrocarbon group which may besubstituted represented by R¹, R² and R³ may have substituent(s).Examples of such substituent include halogen (e.g., fluorine, chlorine,bromine, iodine, etc.), nitro, cyano, oxo, hydroxy group, thiol groupwhich may be substituted (e.g., thiol, C₁₋₄alkylthio, etc.), amino groupwhich may be substituted (e.g., amino, mono-C₁₋₄alkylamino,di-C₁₋₄alkylamino, or 5- or 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, 2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl, etc.),phenyl-lower (C₁₋₄) alkyl, C₃₋₇cycloalkyl, carboxyl group which may beesterified or amidated (e.g., carboxyl, C₁₋₄alkoxy-carbonyl, lower(C₇₋₁₀) aralkyloxy-carbonyl, carbamoyl, mono-C₁₋₄alkyl-carbamoyl,di-C₁₋₄alkyl-carbamoyl, etc.), C₁₋₄alkyl which may be substituted byhalogen atom or C₁₋₄alkoxy (e.g., trifluoromethyl, methyl, ethyl, etc.),C₁₋₄alkoxy which may be substituted by halogen atom or C₁₋₄alkoxy (e.g.,methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.),C₁₋₄alkylenedioxy (e.g., —O—CH₂—O—, —O—CH₂—CH₂—O—, etc.), formyl,C₂₋₄alkanoyl (e.g., acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (e.g.,methanesulfonyl, ethanesulfonyl, etc.), C₁₋₄alkylsulfinyl (e.g.,methanesulfinyl, ethanesulfinyl, etc.), sulfamoyl which may besubstituted (e.g., sulfamoyl, mono-C₁₋₄alkylsulfamoyl,di-C₁₋₄alkylsulfamoyl, etc), an aryl group which may be substituted, aheterocyclic group which may be substituted, and the like. The number ofthe substituents is preferably 1 to 3.

Examples of the “aryl group” in the “aryl group which may besubstituted” as the substituent of the “hydrocarbon group which may besubstituted” represented by R¹, R² and R³ include C₆₋₁₄aryl such asphenyl, naphthyl, etc., preferably C₆₋₁₀aryl, more preferably phenyl,etc.

Examples of the substituent(s) of the “aryl group” include halogen(e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxygroup, thiol group which may be substituted (e.g., thiol, C₁₋₄alkylthio,etc.), amino group which may be substituted (e.g., amino,mono-C₁₋₄alkylamino, di-C₁₋₄alkylamino, or 5- or 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc.), phenyl-lower (C₁₋₄) alkyl,C₃₋₇cycloalkyl, carboxyl group which may be esterified or amidated(e.g., carboxyl, C₁₋₄alkoxy-carbonyl, lower (C₇₋₁₀) aralkyloxy-carbonyl,carbamoyl, mono-C₁₋₄alkyl-carbamoyl, di-C₁₋₄alkyl-carbamoyl, etc.),C₁₋₄alkyl which may be substituted by halogen atom or C₁₋₄alkoxy (e.g.,trifluoromethyl, methyl, ethyl, etc.), C₁₋₄alkoxy which may besubstituted by halogen atom or C₁₋₄alkoxy (e.g., methoxy, ethoxy,trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄alkylenedioxy (e.g.,—O—CH₂—O—, —O—CH₂—CH₂—O—, etc.), formyl, C₂₋₄alkanoyl (e.g., acetyl,propionyl, etc.), C₁₋₄alkylsulfonyl (e.g., methanesulfonyl,ethanesulfonyl, etc.), C₁₋₄alkylsulfinyl (e.g., methanesulfinyl,ethanesulfinyl, etc.), sulfamoyl which may be substituted (e.g.,sulfamoyl, mono-C₁₋₄alkylsulfamoyl, di-C₁₋₄alkylsulfamoyl, etc), aheterocyclic group which may be substituted (e.g., furan, thiophene,pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole,1,2,3-oxadiazole, 1,2,4-oxadizaole, 1,3,4-oxadiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.),and the like. The number of the substituents is preferably 1 to 3.

Examples of the “heterocyclic group which may be substituted” as thesubstituent of the “hydrocarbon group which may be substituted”represented by R¹, R² and R³ include those similar to the “heterocyclicgroup which may be substituted” represented by the above-described R⁶.

In the above-described formula (I), preferred examples of thesubstituent(s) of the “amino group” of the “amino group which may besubstituted” represented by R² include a hydrocarbon group, aheterocyclic group, and an acyl group each of which may be substituted,and the like. When the “amino group” is substituted, the number of thesubstituent(s) is 1 to 2.

Examples of the hydrocarbon group as the substituent of the “amino groupwhich may be substituted” represented by R² include:

(1) alkyl which may be substituted (e.g., C₁₋₁₀alkyl such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.,and preferably lower (C₁₋₆) alkyl, etc.);

(2) cycloalkyl which may be substituted (e.g., C₃₋₈cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, etc.), wherein the cycloalkyl may be condensed with abenzene ring to form indan (e.g., indan-1-yl, indan-2-yl, etc.),tetrahydronaphthalene (e.g., tetrahydronaphthalene-5-yl,tetrahydronaphthalene-6-yl, etc.) etc. (preferably indan etc.), andwherein the cycloalkyl may be crosslinked via a C₁₋₂ linear atomic chainto form a crosslinked cyclic hydrocarbon group such asbicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[3.2.2]nonyl etc. (preferably, cyclohexyl being crosslinked via aC₁₋₂ linear atomic chain, etc., and more preferablybicyclo[2.2.1]heptyl, etc.);(3) alkenyl which may be substituted (e.g., C₂₋₁₀alkenyl such as allyl,crotyl, 2-pentenyl, 3-hexenyl, etc., and preferably lower (C₂₋₆)alkenyl);(4) cycloalkenyl which may be substituted (e.g., C₃₋₇cycloalkenyl suchas 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,2-cyclohexenylmethyl, etc.);(5) alkynyl (e.g., C₂₋₁₀alkynyl such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-pentynyl, 3-hexynyl, etc., preferably lower (C₂₋₆) alkynyl,etc.);(6) aryl (e.g., C₆₋₁₄aryl such as phenyl or naphthyl, etc., preferablyC₆₋₁₀aryl, and more preferably phenyl, etc.);(7) aralkyl (e.g., C₁₋₆alkyl having 1 to 3 C₆₋₁₄allyl groups, preferablyphenyl-C₁₋₄alkyl (e.g., benzyl, phenethyl, etc.); and the like.

Examples of the heterocyclic group as the substituent of the “aminogroup which may be substituted” represented by R² include that similarto the “heterocyclic group” in “heterocyclic group which may besubstituted” as the substituent of the benzene ring of “a furtheroptionally substituted benzene ring” represented by B or C, and in“heterocyclic group which may be substituted” represented by R⁶, and thelike.

Preferred examples of the acyl group as the substituent of the “aminogroup which may be substituted” represented by R² include thatcomprising carbonyl group or sulfonyl group bonded with, for example,(1) hydrogen or a hydrocarbon group (that similar to the hydrocarbongroup as the substituent of the “amino group which may be substituted”represented by the above-described R², etc.), (2) a heterocyclic group(that similar to the heterocyclic group as the substituent of the“heterocyclic group which may be substituted” represented by R², etc.),and the like.

Examples of the substituents of the “hydrocarbon group which may besubstituted”, “heterocyclic group which may be substituted” and “acylgroup which may be substituted” as the substituent of the “amino groupwhich may be substituted” include the “hydrocarbon group which may besubstituted” as the substituent of the benzene ring of “a furtheroptionally substituted benzene ring” represented by B or C and thesubstituent of the “hydrocarbon group” of the “hydrocarbon group whichmay be substituted” represented by R⁶. The number of the substituent(s)is preferably 1 to 3.

In the above-described formula (I), as R¹, hydrogen atom or optionallysubstituted C₁₋₆alkyl are preferred, and hydrogen atom or optionallysubstituted C₁₋₄alkyl are further preferred and, in particular, hydrogenatom is used.

In the above-described formula (I), as the “hydrocarbon group which maybe substituted” represented by R², the group represented by the formula:—X′″—G—(CH₂)_(n)—J wherein X′″ represents C₁₋₄alkylene orC₂₋₄alkenylene, G is a bond, —O—, —S—, —CO—NH— or —NH—CO—, n is aninteger of 0 to 3, J represents an aromatic ring group which may besubstituted, or the group represented by the formula: —X″″—L—(CH₂)_(n)—Mwherein X″″ represents a bond or a C₁₋₄alkylene group, L represents (a)a bond, (b) an aromatic ring group which may be substituted, (c) —O—,(d) —S—, (e) —CO—NH— or (f) —NH—CO—, n is an integer of 0 to 3, and Mrepresents amino group, guanidino group, sulfamoyl group, carbamoylgroup or hydroxyl group are preferred. As the aromatic ring group whichmay be substituted represented by J and L, preferred are an optionallysubstituted phenyl, a 5- or 6-membered monocyclic aromatic heterocyclicgroup, etc.

In the above-described formula (I), as the “hydrocarbon group which maybe substituted” represented by R³, C₁₋₆alkyl which may be substituted ispreferred. Among them, a group represented by the formula: —(CH₂)_(p)—Twherein p is an integer of 1 to 6 and T is an aromatic ring group whichmay be substituted is preferred.

While, as the “aromatic ring group which may be substituted” representedby T, there are the same groups as the “aromatic ring group which may besubstituted” represented by the above-described J, as the substituent ofthe “aromatic ring group” of the “aromatic ring group which may besubstituted” represented by T, preferred are hydroxyl group, sulfamoylgroup which may be substituted (e.g., sulfamoyl,mono-C₁₋₄alkylsulfamoyl, di-C₁₋₄alkyl sulfamoyl, etc.), etc.

In the above-described formula (I), when R¹ and X bind together to forma ring, the ring is not specifically limited in so far as it is anitrogen-containing heterocyclic ring and both saturated and unsaturatedrings are included therein regardless of particular size of the ring.Among them, a 3- to 8-membered nitrogen-containing heterocyclic ring ispreferred and, in particular, a saturated 3- to 8-memberednitrogen-containing heterocyclic ring, i.e., a ring represented by theformula:

wherein D ring represents a saturated 3- to 8-memberednitrogen-containing heterocyclic ring is preferred.

Examples of the “3- to 8-membered nitrogen-containing heterocyclic ring”include a 3- to 8-membered nitrogen-containing heterocyclic ringcontaining one nitrogen atom which may further contain one to threekinds (preferably 1 or 2 kinds) of 1 to 4 (preferably 1 or 2)heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom andthe like. Specific examples thereof include a 3- to 8-membered(preferably 5- to 6-membered) saturated or unsaturated (preferablysaturated) mono-cyclic non-aromatic heterocyclic ring (aliphaticheterocyclic ring) such as pyrrolidine, pyrroline, imidazolidine,imidazoline, pyrazolidine, pyrazoline, oxazine, oxaziadine, thiazine,thiaziadine, piperidine, morpholine, thiomorpholine, piperazine,azepine, etc.

The “3- to 8-membered nitorgen-containing heterocyclic ring” may havesubstituent(s) and examples of the substituents include those similar tothe substituent of the “hydrocarbon group which may be substituted” asthe substituent of the benzene ring of “a further optionally substitutedbenzene ring” represented by the above-described B and C.

Further, in the above-described formula (I), R¹ may bind to the “aminogroup which may be substituted” represented by A to form a ring, and thering is not specifically limited in so far as it is a heterocyclic ringhaving at least 2 nitrogen atoms and may be a saturated or unsaturatedring regardless of particular size of the ring. Among them, a 3- to8-membered nitrogen-containing heterocyclic ring is preferred, inparticular, a saturated 3- to 8-membered heterocyclic ring, i.e., a ringrepresented by the formula:

wherein A′ represents nitrogen atom which may be substituted, and Frepresents a saturated 3- to 8-membered heterocyclic ring.

In the above-described formula, examples of the substituent of the“nitrogen atom” of the “nitrogen atom which may be substituted”represented by A′ include that similar to the substituent of the “aminogroup” of the “amino group which may be substituted” represented by Adescribed hereinafter.

Examples of the “3- to 8-membered nitrogen-containing heterocyclic ring”include a 3- to 8-membered nitrogen-containing heterocyclic ringcontaining two nitrogen atoms which may further contain one to threekinds (preferably 1 or 2 kinds) of 1 to 4 (preferably 1 or 2)heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom andthe like. Specific examples thereof include a 3- to 8-membered(preferably 5- to 6-membered) saturated or unsaturated (preferablysaturated) mono-cyclic non-aromatic heterocyclic ring (aliphaticheterocyclic ring) such as imidazolidine, imidazoline, pyrazolidine,pyrazoline, oxaziadine, thiaziadine, piperazine, diazepine, etc.

The “3- to 8-membered nitorgen-containing heterocyclic ring” may havesubstituent(s) and examples of the substituents include those similar tothe substituent of the “hydrocarbon group which may be substituted” asthe substituent of the benzene ring of “a further optionally substitutedbenzene ring” represented by the above-described B and C.

In the above-described formula, the spacer whose linear chain moiety iscomposed of 1 to 12 atoms represented by X is not specifically limitedin so far as it is a divalent group “whose linear chain moiety iscomposed of 1 to 12 atoms” and examples thereof include a saturateddivalent group such as

(1) —(CH₂)_(f1)— (f1 is an integer of 1 to 12, preferably an integer of1 to 8, more preferably an integer of 1 to 6, in particular, an integerof 1 to 4);

(2) —(CH₂)_(g1)—X¹—(CH₂)_(g2)— (g1 and g2 are the same or different andare integers 0 to 11 provided that the sum of g1 and g2 is 0 to 11, andX¹ is NH, O, S, SO or SO₂);

(3) —(CH₂)_(h1)—X¹—(CH₂)_(h2)—X²—(CH₂)_(h3)— (h1, h2 and h3 are the sameor different integers 0 to 10 provided that the sum of h1, h2 and h3 is0 to 10, and X¹ and X² independently represent NH, O, S, SO or SO₂provided that, when h2 is 0, at least one of X¹ and X² is preferablyNH); etc., and these divalent groups wherein some bonds have beenconverted into unsaturated bonds. Specific examples thereof include adivalent group such as —O—(CH₂)_(k3)— (k3 is an integer of 0 to 11),—(CH₂)_(k3)—O— (k3 is an integer of 0 to 11), —S—(CH₂)_(k3)— (k3 is aninteger of 0 to 11), —(CH₂)_(k3)—S— (k3 is an integer of 0 to 11),—NH—(CH₂)_(k3)— (k3 is an integer of 0 to 11), —(CH₂)_(k3)—NH— (k3 is aninteger of 0 to 11), —(CH₂)_(k4)— (k4 is an integer of 1 to 12),—CH═CH—, —C.C—, —CO—NH—, —SO₂—NH— etc.

More preferably, X is a divalent group whose linear chain moiety iscomposed of 1 to 4 carbon atoms. Among them, preferred are C₁₋₄alkylene,C₂₋₄alkenylene, etc., in particular, C₁₋₄alkylene is preferably used.

The divalent group as X may have substituent(s) at any position(preferably on carbon atom(s)) and such substituent(s) are notspecifically limited in so far as they can bind to the divalent chainwhich constitutes the linear chain moiety. Examples thereof includesubstituents similar to those of the benzene ring in “a furtheroptionally substituted benzene ring” represented by the above-describedB and C, as well as oxo, etc. Such substituent(s) may be the same ordifferent 1 to 4 (preferably 1 to 2) substituents at any position(s) ofthe divalent group. Further, the substituents of the divalent group as Xcan bind to each other to form a ring. Examples of such “ring” includeC₅₋₇cycloalkane such as cyclopentane, cyclohexane, cycloheptane, etc.;benzene; and the like.

Examples of the substituent of the divalent group as X include lower(C₁₋₆) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.); lower(C₃₋₇) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, etc.); formyl; lower (C₂₋₇) alkanoyl (e.g.,acetyl, propionyl butyryl, etc.); lower (C₂₋₇) lower alkoxy-carbonyl;lower (C₁₋₆); lower alkoxy; hydroxy group; oxo, etc.

Examples of “amino group which may be substituted” represented by A inthe above-described formula include amino group which may have one ortwo substituents selected from the group consisting of: “hydrocarbongroup which may be substituted” (e.g., those similar to theabove-described “hydrocarbon group which may be substituted” as thesubstituent of the benzene ring of “a further optionally substitutedbenzene ring” represented by B or C), “heterocyclic group which may besubstituted” (e.g., those similar to the above-described “heterocyclicgroup which may be substituted” as the substituent of the benzene ringof “a further optionally substituted benzene ring” represented by B orC) and “acyl group which may be substituted” (e.g., those similar to theabove-described “acyl group which may be substituted” as the substituentof the benzene ring of “a further optionally substituted benzene ring”represented by B or C), and the like. In the “amino group which may besubstituted” represented by A, the substituents of the amino group maybe bonded to each other to form a cyclic amino group (e.g., a cyclicamino group formed by removing one hydrogen atom from a constituentnitrogen atom of 5- or 6-membered ring such as tetrahydropyrrole,piperazine, piperidine, morpholine, thiomorpholine, pyrrole orimidazole, having a bond on the nitrogen atom). The cyclic amino groupmay have substituent(s), and examples thereof include halogen (e.g.,fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group,thiol group, amino group, carboxyl group, C₁₋₄alkyl which may behalogenated (e.g., trifluoromethyl, methyl, ethyl, etc.), C₁₋₄alkoxywhich may be halogenated (e.g., methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), formyl, C₂₋₄alkanoyl (e.g.,acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (e.g., methanesulfonyl,ethanesulfonyl, etc.), etc. The number of the substituents is preferably1 to 3.

Examples of substituent which the “amino group which may be substituted”represented by A may have preferably include

(1) alkyl which may be substituted (e.g., C₁₋₁₀alkyl such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.,and preferably lower (C₁₋₆) alkyl, etc.);

(2) cycloalkyl which may be substituted (e.g., C₃₋₈cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, etc.), wherein the cycloalkyl may be condensed with abenzene ring to form indan (e.g., indan-1-yl, indan-2-yl, etc.),tetrahydronaphthalene (e.g., tetrahydronaphthalene-5-yl,tetrahydronaphthalene-6-yl, etc.) etc. (preferably indan etc.), andwherein the cycloalkyl may be crosslinked via a C₁₋₂ linear atomic chainto form a crosslinked cyclic hydrocarbon-group such asbicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[3.2.2]nonyl etc. (preferably, cyclohexyl being crosslinked via aC₁₋₂ linear atomic chain, etc., and more preferablybicyclo[2.2.1]heptyl, etc.);(3) alkenyl which may be substituted (e.g., C₂₋₁₀alkenyl such as allyl,crotyl, 2-pentenyl, 3-hexenyl, etc., and preferably lower (C₂₋₆)alkenyl);(4) cycloalkenyl which may be substituted (e.g., C₃₋₇cycloalkenyl suchas 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,2-cyclohexenylmethyl, etc.);(5) aralkyl which may be substituted (e.g., phenyl-C₁₋₄alkyl such asbenzyl, phenethyl, etc.);(6) formyl or acyl which may be substituted (e.g., C₂₋₄alkanoyl such asacetyl, propionyl, butyryl, isobutyryl, etc., and C₁₋₄alkylsulfonyl suchas methanesulfonyl, ethanesulfonyl, etc.);(7) aryl which may be substituted (e.g., phenyl, naphthyl, etc.);(8) heterocyclic group which may be substituted (e.g., a group formed byeliminating one hydrogen atom from a 5- or 6-membered aromaticheterocyclic ring comprising 1 to 4 heteroatom(s) of 1 or 2 speciesselected from the nitrogen, sulfur and oxygen atoms (e.g. furan,thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole,isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine,triazine, etc.); and a group formed by eliminating one hydrogen atomfrom a 5- or 6-membered non-aromatic heterocyclic ring comprising 1 to 4heteroatom(s) of 1 or 2 species selected from the nitrogen, sulfur andoxygen atoms (e.g. tetrahydrofuran, tetrahydrothiophene, dithiolane,oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline,pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine,thiazine, thiadiazine, morpholine, thiomorpholine, pyran,tetrahydropyran, etc.)).

Examples of the substituents of the above-described (1) alkyl which maybe substituted, (2) cycloalkyl which may be substituted, (3) alkenylwhich may be substituted, (4) cycloalkenyl which may be substituted, (5)aralkyl which may be substituted, (6) acyl which may be substituted, (7)aryl which may be substituted, and (8) heterocyclic group which may besubstituted include halogen (e.g., fluorine, chlorine, bromine, iodine,etc.); C₁₋₄alkyl which may be substituted by halogen atom or C₁₋₄alkoxy;C₁₋₄alkoxy which may be substituted by halogen atom or C₁₋₄alkoxy (e.g.,methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy,etc.); C₁₋₄alkylenedioxy (e.g., —O—CH₂—O—, —O—CH₂—CH₂—O—, etc.); formyl,C₂₋₄alkanoyl (e.g., acetyl, propionyl, etc.); C₁₋₄alkylsulfonyl (e.g.,methanesulfonyl, ethanesulfonyl, etc.); phenyl-lower (C₁₋₄) alkyl;C₃₋₇cycloalkyl; cyano; nitro; hydroxy group; thiol group which may besubstituted (e.g., thiol, C₁₋₄alkylthio, etc.); amino group which may besubstituted (e.g., amino, mono-C₁₋₄alkylamino, di-C₁₋₄alkylamino, 5- or6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.);carboxyl group; lower (C₁₋₄) alkoxy-carbonyl; lower (C₇₋₁₀)aralkyloxy-carbonyl; carbamoyl; mono-C₁₋₄alkyl-carbamoyl;di-C₁₋₄alkyl-carbamoyl (preferably halogen, lower (C₁₋₄) alkyl which maybe halogenated, lower (C₁₋₄) alkoxy which may be halogenated,phenyl-lower (C₁₋₄)alkyl, C₃₋₇cycloalkyl, cyano, hydroxy group, etc.);etc. The number of the substituents is preferably 1 to 3.

Particularly, examples of “amino group which may be substituted”represented by A include amino group which may have one or two alkylwhich may be substituted [e.g., C₁₋₁₀alkyl (such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, preferablylower (C₁₋₆) alkyl) which may have 1 to 3 substituent(s) selected fromthe group consisting of halogen (e.g., fluorine, chlorine, bromine,iodine, etc.), nitro, cyano, hydroxy group, thiol group which may besubstituted (e.g., thiol, C₁₋₄alkylthio, etc.), amino group which may besubstituted (e.g., amino, mono-C₁₋₄alkylamino, di-C₁₋₄alkylamino, 5- or6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.),carboxyl group which may be esterified or amidated (e.g., carboxyl,C₁₋₄alkoxy-carbonyl, lower (C₇₋₁₀) aralkyloxy-carbonyl, carbamoyl,mono-C₁₋₄alkyl-carbamoyl or di-C₁₋₄alkyl-carbamoyl), C₁₋₄alkyl which maybe substituted by halogen atom or C₁₋₄alkoxy (e.g., trifluoromethyl,methyl, ethyl, etc.), C₁₋₄alkoxy which may be substituted by halogenatom or C₁₋₄alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄alkylenedioxy (e.g., —O—CH₂—O—,—O—CH₂—CH₂—O—, etc.), phenyl-lower (C₁₋₄) alkyl, C₃₋₇cycloalkyl, formyl,C₂₋₄alkanoyl (e.g., acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (e.g.,methanesulfonyl, ethanesulfonyl, etc.) or C₁₋₄alkylsulfinyl (e.g.,methanesulfinyl, ethanesulfinyl, etc.), etc.].

In the above-described formula, examples of the “nitrogen-containingheterocyclic group” of the “nitrogen-containing heterocyclic group whichmay be substituted” represented by A include those which may be formedby removing one hydrogen atom from a 5- to 8-membered aromaticmonocyclic heterocyclic ring, saturated or unsaturated non-aromaticmonocyclic heterocyclic ring (aliphatic heterocyclic ring), etc.containing one nitrogen atom and further 1 to 4 (preferably 1 or 2) of 1to 3 (preferably 1 or 2) kinds of heteroatom(s) selected from the groupconsisting of oxygen, sulfur and nitrogen atoms; a ring formed bycondensing the same or different rings selected from these monocyclicrings; or the like. While the “nitrogen-containing heterocyclic groupwhich may be substituted” represented by A may bind to X through any ofnitrogen atom or carbon atom, preferably, it binds to X through carbonatom.

Examples of “aromatic monocyclic heterocyclic ring” include a 5- to8-membered (preferably 5- or 6-membered) aromatic monocyclicheterocyclic ring (e.g., pyrrole, oxazole, isoxazole, thiazole,isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,3,4-thiadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, triazine, etc.). Examples of“non-aromatic monocyclic heterocyclic ring” include a 5- to 8-membered(preferably 5- or 6-membered) saturated or unsaturated monocyclicnon-aromatic heterocyclic ring (aliphatic heterocyclic ring) such aspyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine,pyrazoline, oxazine, oxadiazine, thiazine, thiadiazine, piperidine,morpholine, thiomorpholine, piperazine, azepine, etc.; a 5- to8-membered non-aromatic heterocyclic ring comprising any of theabove-described aromatic monocyclic heterocyclic rings with all orportion of double bonds therein being saturated; and the like.

Examples of the substituent of the “nitrogen-containing heterocyclicring” of the “nitrogen-containing heterocyclic ring which may besubstituted” represented by A include that similar to theabove-described substituent of the “hydrocarbon group which may besubstituted” as the substituent of the benzene ring of “a furtheroptionally substituted benzene ring” represented by B or C.

As the “nitrogen-containing heterocyclic group” of the“nitrogen-containing heterocyclic group” represented by A, a 5- to6-membered nitrogen-containing heterocyclic group is preferred and asaturated 5- to 6-membered nitrogen-containing heterocyclic group ismore preferred. Among them, particularly preferred are pyrrolidine,piperidine, piperazine (preferably a saturated 5- to 6-memberednitrogen-containing heterocyclic ring), etc.

In the above-described formula, preferred examples of the grouprepresented by the formula:

include a group represented by the formula:

wherein R¹ is as defined above, X′ represents C₁₋₆alkylene group whichmay be substituted, R⁴ and R⁵ are hydrogen atom or C₁₋₆alkyl group whichmay be substituted, respectively, and R⁴ and R⁵ bind to each other toform a ring, a group represented by the formula:

wherein X″ is a bond or C1–4alkylene group which may be substituted,ring D and ring E represent a saturated 3- to 8-memberednitrogen-containing heterocyclic ring, respectively; and the like.

Examples of the substituent of “C₁₋₆alkylene group (preferablyC₁₋₄alkylene group)” in the “C₁₋₆alkylene group which may besubstituted” represented by X′ include that similar to the substituentof the divalent group as X.

In the above-described formula, examples of the “C₁₋₆alkyl group whichmay be substituted” represented by R⁴ and R⁵ include lower (C₁₋₆) alkylgroup such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., whichmay have 1 to 3 substituent(s) selected from the group consisting ofhalogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, thiol group which may be substituted (e.g., thiol orC₁₋₄alkylthio), amino group which may be substituted (e.g., amino,mono-C₁₋₄alkylamino, di-C₁₋₄alkylamino, 5- or 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc.), carboxyl group which may beesterified or amidated (e.g., carboxyl, C₁₋₄alkoxy-carbonyl, lower(C₇₋₁₀) aralkyloxy-carbonyl, carbamoyl, mono-C₁₋₄alkyl-carbamoyl,di-C₁₋₄alkyl-carbamoyl, etc.), C₁₋₄alkyl which may be substituted byhalogen atom or C₁₋₄alkoxy (e.g., trifluoromethyl, methyl, ethyl, etc.),C₁₋₄alkoxy which may be substituted by halogen atom or C₁₋₄alkoxy (e.g.,methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.),C₁₋₄alkylenedioxy (e.g., —O—CH₂—O—, —O—CH₂—CH₂—O—, etc.), phenyl-lower(C₁₋₄) alkyl, C₃₋₇cycloalkyl, formyl, C₂₋₄alkanoyl (e.g., acetyl,propionyl, etc.), C₁₋₄alkylsulfonyl (e.g., methanesulfonyl,ethanesulfonyl, etc.), C₁₋₄alkylsulfinyl (e.g., methanesulfinyl,ethanesulfinyl, etc.) and the like.

In the above-described formula, R⁴ and R⁵ may bind to each other to formtogether with the adjacent nitrogen atom a cyclic amino group (e.g., acyclic amino group formed by removing one hydrogen atom from constituentnitrogen atom of a 5- or 6-membered ring with a bond on its nitrogenatom, such as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc.; preferably a saturated 5- to6-membered cyclic amino group such as pyrrolidino, piperazino,piperidino, etc.; more preferably pyrrolidino, etc.). The cyclic aminogroup may have substituent(s) and examples thereof include halogen(e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxygroup, thiol group, amino group, carboxyl group, C₁₋₄alkyl which may behalogenated (e.g., trifluoromethyl, methyl, ethyl, etc.), C₁₋₄alkoxywhich may be halogenated (e.g., methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), formyl, C₂₋₄alkanoyl (e.g.,acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (e.g., methanesulfonyl,ethanesulfonyl, etc.), etc. The number of the substituents is preferably1 to 3.

In the above-described formula, examples of the substituent of the“C₁₋₄alkylene group” of the “C₁₋₄alkylene group which may besubstituted” include that similar to the substituent of the divalentgroup as X.

Examples of the “saturated 3- to 8-membered nitrogen-containingheterocyclic ring represented by X” include a 3- to 8-memberednitrogen-containing heterocyclic ring containing one nitrogen atom whichmay further contain one to three kinds (preferably 1 or 2 kinds) of 1 to4 (preferably 1 or 2) heteroatoms selected from oxygen atom, sulfur atomand nitrogen atom and the like. Specific examples thereof include a 3-to 8-membered (preferably 5- to 6-membered) saturated or unsaturated(preferably saturated) mono-cyclic non-aromatic heterocyclic ring(aliphatic heterocyclic ring) such as pyrrolidine, pyrroline,imidazolidine, imidazoline, pyrazolidine, pyrazoline, oxazine,oxaziadine, thiazine, thiaziadine, piperidine, morpholine,thiomorpholine, piperazine, azepine, etc.

The “3- to 8-membered nitrogen-containing heterocyclic ring” may havesubstituent(s) and examples of the substituents include those similar tothe substituent of the “hydrocarbon group which may be substituted” asthe substituent of the benzene ring of “a further optionally substitutedbenzene ring” represented by the above-described B and C.

Further, while the “3- to 8-membered nitrogen-containing heterocyclicgroup which may be substituted” represented by ring D and ring E maybind to X″ through any of nitrogen atom or carbon atom, preferably, itbinds to X″ through carbon atom.

In the above-described formula (I), while the substituents of ring B andring C shown in the formula may be substituted at any possiblepositions, preferably, a compound represented by the formula (I) or asalt thereof has any of the following structures:

wherein each symbol is as defined above.

Among them, preferably, the compound has the following structure:

In particular, among the compounds represented by the formula (I),3′-{[{2-[4-(aminosulfonyl)phenyl]ethyl}(4-phenylbutanoyl)amino]methyl}-N-[2-(1-pyrrolidinyl)ethyl]-[1,1′-biphenyl]-3-carboxamide,3′-({{2-[4-(aminosulfonyl)phenyl]ethyl}-[(benzyloxy)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)-ethyl][1,1′-biphenyl]-3-carboxamide,N-(2-aminoethyl)-3′-{[[3-({[amino(imino)methyl]-amino}methyl)benzoyl](1-naphthylmethyl)amino]methyl}-1,1′-biphenyl]-2-carboxamide,N-(2-Aminoethyl)-3′-{[[4-(aminosulfonyl)benzoyl]-(1-naphthylmethyl)amino]methyl}-1,1′-biphenyl-2-carboxamide,and the like are preferably used.

Salts of the compound represented by the formula (I) and used in thepresent invention are preferably pharmaceutically acceptable salts, forexample, salts with inorganic base, organic base, inorganic acid,organic acid, or basic or acidic amino acid.

Preferred examples of salts with inorganic base include alkaline metalsalts such as sodium salts or potassium salts; alkaline earth metalsalts such as calcium salts or magnesium salts; and aluminium salts andammonium salts, etc.

Preferred examples of salts with organic base include salts with, forexample, trimethylamine, triethylamine, pyridine, picoline,ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine orN,N′-dibenzylethylenediamine, etc.

Preferred examples of salts with inorganic acid include salts with, forexample, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acidor phosphoric acid, etc.

Preferred examples of salts with organic acid include salts with, forexample, formic acid, acetic acid, trifluoroacetic acid, fumaric acid,oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,malic acid, methansulfonic acid, benzenesulfonic acid orp-toluenesulfonic acid, etc.

Preferred examples of salts with basic amino acid include salts with,for example, arginine, lysine or ornithine, etc. Preferred examples ofsalts with acidic amino acid include salts with, for example, asparticacid or glutamic acid, etc.

The compound represented by the formula (I) to be used in the presentinvention may be hydrates or non-hydrates. Further, the compoundrepresented by the formula (I) to be used in the present invention canbe individually isolated by any known means for separation and/orpurification as desired when it is present as configurational isomers,diastereoisomers or conformers. Furthermore, the compound represented bythe formula (I) to be used in the present invention can be separatedinto S-form and R-form by any conventional optical resolution means whenit is present as racemic modifications. All of those optically activesubstances and racemic modifications are encompassed by the presentinvention.

The compound represented by the formula (I) to be used in the presentinvention and a salt thereof [hereinafter sometimes referred to ascompound (I)] may be used as prodrugs. Examples of such prodrugs mayinclude a compound which may be converted into compound (I) through, forexample, enzyme- or gastric acid-mediated reaction in vivo underphysiological conditions, i.e., a compound which may be enzymaticallyoxidized, reduced and/or hydrolyzed to be converted into compound (I),and a compound which may be hydrolyzed by gastric acid and the like tobe converted into compound (I). Examples of the prodrug of compound (I)include a compound such as compound (I) whose amino group has beenacylated, alkylated or phosphorylated (e.g., a compound such as compound(I) whose amino group has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,tert-butylated, etc.); a compound such as compound (I) whose hydroxygroup has been acylated, alkylated, phosphorylated or borated (e.g., acompound such as compound (I) whose hydroxy group has been acetylated,palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated,alanylated, dimethylaminomethylcarbonylated, etc.); a compound such ascompound (I) whose carboxyl group has been esterified or amidated (e.g.,a compound such as compound (I) whose carboxyl group has been ethylesterified, phenyl esterified, carboxymethyl esterified,dimethylaminomethyl esterified, pivaloyloxymethyl esterified,ethoxycarbonyloxyethyl esterified, phthalidyl esterified,(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl esterified,cyclohexyloxycarbonylethyl esterified, methylamidated, etc.), etc. Thesecompounds can be prepared from compound (I) using any known method.

Further, prodrugs of compound (I) may be compounds which may beconverted into compound (I) under physiological conditions as describedin “Development of pharmaceuticals (Iyakuhinn no Kaihatsu)”, vol. 7,Molecular Design pp. 163–198, Hirokawa Shoten (1990).

Furthermore, compound (I) may be labeled with any suitable isotope suchas ³H, ¹⁴C, ³⁵S, ¹²⁵I, etc.

Compound (I) of the present invention may be used alone or incombination with pharmaceutically acceptable carrier or carriers, toformulate solid preparations such as tablet, capsule, granule, powder,etc.; or liquid preparations such as syrup, injectable preparation,etc., which can then be administered orally or parenterally.

Dosage forms for parenteral administration include, for example,injectable preparations, instillation and suppository.

Examples of pharmaceutically acceptable carrier include various organicor inorganic carrier materials which have been conventionally used asformulation bases. Excipient, lubricant, binder, disintegrator, etc.,may be used for solid preparations, while solvent, dissolution adjuvant,suspending agent, isotonizing agent, buffer, soothing agent, etc., maybe used for liquid preparations. Additive or additives may be added whenrequired, including preservative, anti-oxidant, colorant, sweeteningagent, etc. Preferred examples of excipient include lactose, saccharose,D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid,etc. Preferred examples of lubricant include, for example, magnesiumstearate, calcium stearate, talc, colloidal silica, etc. Preferredexamples of binder include, for example, crystalline cellulose,saccharose, D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc. Preferredexamples of disintegrator include, for example, starch, carboxymethylcellulose, carboxy methylcellulose calcium, crosscarmellose sodium,sodium carboxymethyl starch, etc. Preferred examples of solvent include,for example, water for injection, alcohol, propylene glycol, macrogol,sesame oil, corn oil, etc. Preferred examples of dissolution adjuvantinclude, for example, polyethylene glycol, propylene glycol, D-mannitol,benzyl benzoate, ethanol, trisaminomethane, cholesterol,triethanolamine, sodium carbonate, sodium citrate, etc. Preferredexamples of suspending agent include: surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylamino propionate, lecitin,benzalkonium chloride, benzethonium chloride, glyceryl monostearate,etc; and hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, etc. Preferred examples of isotonizing agent include, forexample, sodium chloride, glycerine, D-mannitol, etc. Preferred examplesof buffer include buffer solution of, for example, phosphate, acetate,carbonate, citrate, etc. Preferred examples of soothing agent include,for example, benzyl alcohol, etc. Preferred examples of preservativeinclude, for example, p-hydroxybenzoic esters, chlorobutanol, benzylalcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.Preferred examples of anti-oxidant include, for example, sulfite,ascorbic acid, etc.

A process for producing a compound represented by the formula (I) or asalt thereof will be described below. Starting compounds andintermediates shown in the following process may form their saltssimilar to those of a compound represented by the formula (I).

Production Process

A compound represented by the formula (I) or a salt thereof can beproduced, for example, according to Scheme 1:

wherein each symbol is as defined above.

The compound represented by the formula (I) or a salt thereof can beproduced by reacting a compound represented by the formula (II) and acarboxylic acid represented by the formula: R²COOH, a reactivederivative thereof or a salt thereof in a solvent, if necessary, in thepresence of a base, by using a condensation agent. Examples of thereactive derivative of the carboxylic acid include acid anhydrides,active esters (e.g., p-nitrophenyl ester, N-hydroxysuccinimide ester,pentafluorophenyl ester, 1-hydroxybenzotriazol ester, etc.), acidhalides (e.g., acid chloride, acid bromide, etc.), imidazolides andmixed acid anhydrides (e.g., anhydride with methyl carbonate, anhydridewith ethyl carbonate, etc.), etc. Specific examples thereof include acompound whose group corresponding to that represented by the formula—COOH is a group represented by the formula —COQ [wherein, Q is aleaving group (e.g., a halogen atom (fluorine, chlorine, bromine,iodine, etc.), methanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, etc.)], etc. Examples of the solvent to be usedinclude ether solvents (e.g., diethyl ether, tetrahydrofuran, dioxane,etc.), hydrocarbon solvents (e.g., benzene, toluene, hexane, heptane,etc.), halogen solvents (e.g., dichloromethane, dichloroethane,chloroform, tetrachloromethane, etc.), acetonitrile,N,N-dimethylformamide, etc. Examples of the base to be used includeorganic bases such as triethylamine, 4-dimethylaminopyridine,N,N-diisopropylethylamine, triethylenediamine, and 4-methylmorpholine,carbonates of alkali metals or alkali earth metals (e.g., sodiumcarbonate, potassium carbonate, etc.), hydrogencarbonates of alkalimetals or alkali earth metals (e.g., sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.), hydroxides of alkali metals or alkali earthmetals (e.g., sodium hydroxide, potassium hydroxide, etc.), etc. As thecondensation agent to be used, there are those used for peptidesynthesis, etc. Specific examples thereof includedicyclohexylcarbodiimide, diisopropylcarbodiimide,N-ethyl-N′-3-dimethylaminopropylcarbodiimide and hydrochloride thereof,benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate,benzotriazol-1-yl-trispyrrolidinophosphonium hexafluorophosphate,diethyl cyanophosphate, diphenylphosphorylazide,N-hydroxy-5-norbornene-2,3-carboxyimide, etc. These may be used alone orin combination with 1-hydroxybenzotriazol, 1-hydroxy-7-azabenzotriazol,etc. In this case, the carboxylic acid represented by the formula:R²COOH or a salt thereof is used in an amount of 0.5 to 10 moleequivalents, preferably 1 to 5 mole equivalents, and the condensationagent is used in an amount of 0.5 to 10 mole equivalents, preferably 1to 6 equivalent, based on 1 mole of the compound represented by theformula (II) or a salt thereof. In this case, the reaction temperatureis −50 to 200° C., preferably −20 to 100° C., and the reaction time is0.5 to 96 hours, preferably from 0.5 to 72 hours, more preferably from 1to 24 hours.

A compound expressed by the formula (I) or a salt thereof can also beproduced, for example, according to Scheme 2:

wherein each symbol is as defined above.

The compound represented by the formula (I) or a salt thereof can beproduced by reacting a compound represented by the formula (III), areactive derivative thereof or a salt thereof, and a compoundrepresented by the formula (IV) or a salt thereof in a solvent, ifnecessary, in the presence of a base, by means of a condensation agent.Examples of the reactive derivative of the compound represented by theformula (III) include acid anhydrides, active esters (e.g.,p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenylester, 1-hydroxybenzotriazol ester, etc.), acid halides (e.g., acidchloride, acid bromide, etc.), imidazolides, mixed acid anhydrides(e.g., anhydride with methyl carbonate, anhydride with ethyl carbonate,etc.), etc. Specific examples thereof include a compound whose groupcorresponding that represented by the formula: —COOH is a grouprepresented by the formula: —COQ [wherein, Q is a leaving group (e.g.,halogen atom (fluorine, chlorine, bromine, iodine, etc.),methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.)],etc. Examples of the solvent to be used include ether solvents (e.g.,diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbon solvents(e.g., benzene, toluene, hexane, heptane, etc.), halogen solvents (e.g.,dichloromethane, dichloroethane, chloroform, tetrachloromethane, etc.),acetonitrile, N,N-dimethylformamide, etc. Examples of the base to beused include organic bases such as triethylamine,4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylenediamine,and 4-methylmorpholine, carbonates of alkali metals or alkali earthmetals (e.g., sodium carbonate, potassium carbonate, etc.),hydrogencarbonates of alkali metals or alkali earth metals (e.g., sodiumhydrogencarbonate, potassium hydrogencarbonate, etc.), hydroxides ofalkali metals or alkali earth metals (e.g., sodium hydroxide, potassiumhydroxide, etc.), etc. As the condensation agent to be used, there arethose for use in peptide synthesis, etc. Specific examples thereofinclude dicyclohexylcarbodiimide, diisopropylcarbodiimide,N-ethyl-N′-3-dimethylaminopropylcarbodiimide and hydrochloride thereof,benzotriazol-1-yl-tris(dimethylamino)phosphoniumhexafluorophosphate,benzotriazol-1-yl-trispyrrolidinophosphoniumhexafluorophosphate, diethylcyanophosphate, diphenylphosphorylazide, etc. These may be used alone orin combination with 1-hydroxybenzotriazol, 1-hydroxy-7-azabenzotriazol,etc. In this case, the compound represented by the formula (IV) or asalt thereof is used in an amount of 0.5 to 10 mole equivalents,preferably 1 to 5 mole equivalents, and the condensation agent is usedin an amount of 0.5 to 10 mole equivalents, preferably 1 to 6 moreequivalents, based on 1 mole of a compound represented by the formula(III) or a salt thereof. In this case, the reaction temperature is −50to 200° C., preferably −20 to 100° C., and the reaction time is 0.5 to96 hours, preferably 0.5 to 72 hours, and more preferably 1 to 24 hours.

A compound expressed by the formula (II) or a salt thereof can beproduced, for example, according to Scheme 3:

wherein W represents a halogen atom (for example, fluorine, chlorine,bromine, iodine, etc.) or trifluoromethanesulfonyloxy group, and each ofthe other symbols is as defined above.

A compound represented by the formula (VI) or a salt thereof can beproduced by reacting a compound represented by the formula (V), areactive derivative thereof or a salt thereof, with a compoundrepresented by the formula (IV) or a salt thereof. This reaction iscarried out under the same conditions, etc. as those for thecondensation reaction in the above-described Scheme 2 above.

The compound represented by the formula (VII) or a salt thereof can beproduced by reacting a compound represented by the formula (VI) or asalt thereof with formylbenzeneboronic acid or ester thereof oranhydride thereof in a solvent under basic conditions in the presence ofa transition metal catalyst. Examples of the solvent to be used includewater, alcohol solvents (e.g., methanol, ethanol, n-propanol,isopropanol, etc.), ether solvents (e.g., diethyl ether,tetrahydrofuran, 1,2-dimethoxyethane, etc.), hydrocarbon solvents (e.g.,benzene, toluene, hexane, heptane, etc.), N,N-dimethylformamide, etc.These solvents may be used alone or, as necessary, as a mixture preparedby mixing two species or more in appropriate ratios. Examples of thebase to be used include carbonates of alkali metals or alkali earthmetals (e.g., sodium carbonate, potassium carbonate, etc.),hydrogencarbonates of alkali metals or alkali earth metals (e.g., sodiumhydrogencarbonate, potassium hydrogencarbonate, etc.), hydroxides ofalkali metals or alkali earth metals (e.g., sodium hydroxide, potassiumhydroxide, etc.), triethylamine, 4-dimethylaminopyridine,N,N-diisopropylethylamine, triethylenediamine, 4-methylmorpholine, etc.Examples of the transition metal catalyst to be used include palladiumcatalysts [e.g., tetrakis(triphenylphosphine)palladium,1,1-bis(diphenylphosphine)ferrocene dichloropalladium,dichlorobis(triphenylphosphine)palladium etc.], etc. In this case,formylbenzeneboronic acid or ester thereof or anhydride thereof is usedin an amount of 0.5 to 10 mole equivalents, preferably 1 to 5 moleequivalents, and the transition metal catalyst is used in an amount of0.01 to 1 mole equivalent, preferably 0.05 to 0.2 equivalent, based on 1mole of the compound represented by the formula (VI) or a salt thereof.In this case, the reaction temperature is 0 to 200° C., preferably 50 to100° C., and the reaction time is 0.5 to 48 hours, preferably 1 to 24hours.

The compound represented by the formula (II) or a salt thereof can beproduced by reacting a compound represented by the formula (VII) or asalt thereof and an amine represented by the formula: R³NH₂ or a saltthereof under reductive amination conditions. This reductive aminationcan be carried out by reacting a compound represented by the formula(VII) or a salt thereof with the amine represented by the formula: R³NH₂or a salt thereof in the presence of a metal hydrogen complex (e.g.,sodium boron hydride, cyano sodium boron hydride, triacetoxy sodiumboron hydride, etc.) in a solvent such as an ether solvent (e.g.,diethyl ether, tetrahydrofuran, dioxane, etc.), a hydrocarbon solvent(e.g., benzene, toluene, hexane, heptane, etc.), a halogen solvent(e.g., dichloromethane, dichloroethane, chloroform, tetrachloromethane,etc.), an alcohol solvent (e.g., methanol, ethanol, n-propanol,isopropanol, etc.), acetonitrile, N,N-dimethylformamide or acetic acid,etc., or in a mixed solvent thereof. In this case, the amine representedby the formula: R³NH₂ or a salt thereof is used in an amount of 0.5 to10 mole equivalents, preferably 1 to 5 mole equivalents, and the metalhydrogen complex is used in an amount of 0.5 to 10 mole equivalents,preferably 1 to 5 equivalents, based on 1 mole of a compound indicatedby the formula (VII) or a salt thereof. In this case, the reactiontemperature is 0 to 200° C., preferably 20 to 100° C., and the reactiontime is 0.5 to 96 hours, preferably 1 to 24 hours.

The compound represented by the formula (II) or a salt thereof can alsobe produced, for example, in accordance with Scheme 4:

wherein R⁵ represents C₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc., which may besubstituted, and each of the other symbols is as defined above.

A compound represented by the formula (IX) or a salt thereof can beproduced by reacting a compound represented by the formula (VIII) or asalt thereof with formylbenzeneboronic acid or ester thereof oranhydride thereof in a solvent under basic conditions in the presence ofa transition metal catalyst. This reaction is carried out under the sameconditions, etc. as those illustrated in the reaction from the compoundrepresented by the formula (VI) or a salt thereof to the compoundrepresented by the formula (VII) or a salt thereof in theabove-described Scheme 3.

A compound represented by the formula (X) or a salt thereof can beproduced by reacting a compound represented by the formula (IX) or asalt thereof with an amine represented by the formula: R³NH₂ or a saltthereof under reductive amination conditions. This reaction is carriedout under the same conditions, etc. as those illustrated in the reactionfrom the compound represented by the formula (VII) or a salt thereof tothe compound represented by the formula (II) or a salt thereof in theabove-described Scheme 3.

A compound represented by the formula (XI) or a salt thereof can beproduced by treating the compound represented by the formula (X) or asalt thereof with an acid or base. That is, the desired compound or asalt thereof can be produced by the reaction of the compound representedby the formula (X) or a salt thereof, and a mineral acid (e.g., nitricacid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid,etc.) or a hydroxide of an alkali metal (e.g., sodium hydroxide,potassium hydroxide, lithium hydroxide, etc.) in a solvent, for example,water, an ether solvent (e.g., diethyl ether, tetrahydrofuran, dioxane,etc.), an alcohol solvent (e.g., methanol, ethanol, n-propanol,isopropanol, etc.), etc., or in a mixed solvent thereof, at 0 to 150°C., preferably at 20 to 50° C. In this case, the strength of the acid orbase is suitably about 0.1 to 10 N, and the reaction time is 1 to 72hours.

The compound represented by the formula (II) or a salt thereof can beproduced by reacting the compound represented by the formula (XI), areactive derivative thereof or a salt thereof with the compoundrepresented by the formula (IV) or a salt thereof. This reaction iscarried out under the same conditions, etc. as those illustrated in theabove-described condensation reaction of Scheme 2.

The compound represented by the formula (III) or a salt thereof can beproduced, for example, according to Scheme 5:

wherein each symbol is as defined above.

A compound represented by the formula (XII) or a salt thereof can beproduced by reacting the compound represented by the formula (X), whoseproduction process has been illustrated in the above-described Scheme 4,with the carboxylic acid represented by the formula: R²COOH, a reactivederivative thereof or a salt thereof in a solvent, if necessary, in thepresence of a base using a condensation agent. This reaction uses iscarried out under the same conditions, etc., as those illustrated in thecondensation reaction of the above-described Scheme 1.

The compound represented by the formula (III) or a salt thereof can beproduced by treating the compound represented by Formula (XII) or a saltthereof with an acid or base. This reaction is carried out under thesame conditions, etc., as those illustrated in the reaction from thecompound represented by the formula (X) or a salt thereof to thecompound represented by the formula (XI) or a salt thereof in theabove-described Scheme 4.

Compound (I) obtained in this manner can be isolated and purified bymeans of a known separation and purification means such as, for example,condensation, vacuum concentration, solvent extraction, crystallization,recrystallization, conversion dissolution, chromatography, etc.

The compounds used in each of the above-described production processesmay form salts similar to those of compound (I) in so far as they do notinterfere with the reaction.

Further, in each of the above-described reactions, when a startingcompound has as a substituent amino group, carboxyl group, or hydroxylgroup, it may be protected by introducing a protective group generallyused in peptide chemistry, etc. and the desired compound can be obtainedby removing the protective group, if necessary, after the reaction.

Examples of the protective group for amino group to be used includeC₁₋₆alkyl carbonyl (e.g., acetyl, propionyl, etc.), formyl,phenylcarbonyl, C₁₋₆alkyloxycarbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, t-butoxycarbonyl, etc.) phenyloxycarbonyl (e.g.,benzoxycarbonyl, etc.), C₇₋₁₀aralkyloxycarbonyl (e.g.,benzyloxycarbonyl, etc.), trityl, phthaloyl, etc., each of which may besubstituted. Examples of the substituent(s) to be used include a halogenatom (e.g., fluorine, chlorine, bromine, iodine, etc.), C₁₋₆alkylcarbonyl (e.g., acetyl, propionyl, butyryl, etc.), nitro group, etc.,and the number of substituents is about 1 to 3.

Examples of the protective group for carboxyl group to be used includeC₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,etc.), phenyl, trityl, silyl, etc., each of which may be substituted.Examples of the substituent(s) to be used include a halogen atom (e.g.,fluorine, chlorine, bromine, iodine, etc.), C₁₋₆alkyl carbonyl (e.g.,acetyl, propionyl, butyryl, etc.), formyl, nitro group, etc., and thenumber of substituents is about 1 to 3.

Examples of the protective group for hydroxyl group to be used includeC₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,etc.), phenyl, C₇₋₁₀aralkyl (e.g., benzyl, etc.), C₁₋₆alkyl carbonyl(e.g., acetyl, propionyl, etc.), formyl, phenyloxycarbonyl,C₇₋₁₀aralkyloxycarbonyl (e.g., benzyloxycarbonyl, etc.), pyranyl,furanyl and silyl, each of which may be substituted. Examples of thesubstituent(s) to be used include a halogen atom (e.g., fluorine,chlorine, bromine, iodine, etc.), C₁₋₆alkyl, phenyl, C₇₋₁₀aralkyl, nitrogroup, etc., and the number of substituent groups is about 1 to 4.

In addition, while a per se known method or a modification methodthereof (for example, the method described in Protective Groups inOrganic Chemistry (J. F. W. MacOmie et al., Plenum Press Corp.) can beused as a method of introducing or removing the protective group, as aremoving method, for example, there can be used a method whereintreatment is carried out with an acid, a base, reduction, ultravioletray, hydrazine, phenylhydrazine, sodium N-methylthiocarbamate,tetrabutylammonium fluoride, palladium acetate, etc.

Since compound (I) of the present invention has a potent GPR 14antagonizing activity, it can be used as a therapeutic agent forexpressing various vasoactivities (such as accentuation or inhibition ofvasoconstriction), and preferably as a vasoconstriction inhibitor.

Further, compound (I) of the present invention can be used as an agentfor preventing and/or treating various diseases (e.g., circulatorysystem-associated diseases). Among them, it is preferably used as anagent for preventing and/or treating hypertension, arteriosclerosis,hypertension, hypercardia, myocardial infarction, heart failure, septicshock, etc., in particular, an agent for preventing and/or treatingischemic myocardial infarction or congestive heart failure.

Further, compound (I) of the present invention has very low toxicity andthus can be used safely.

Daily dose of compound (I) of the present invention as a GPR 14antagonist may depend on various factors such as the condition andweight of the patient to be treated and administration manner. For oraladministration, the compound may be administered at an amount of about0.1 to 100 mg, preferably about 1 to 50 mg, more preferably about 1 to20 mg as an active component [(e.g., compound (I)] per an adult (50 kg)and it can be administered once to three times a day.

Compound (I) of the present invention may be used in combination withother therapeutic agent(s) (particularly with a therapeutic agent forpreventing and/or treating hypertension, etc.). In this case, theseagents may separately be formulated into different preparations, or maybe formulated together into one preparation, by blending with anypharmaceutically acceptable carrier, excipient, binder and/or diluent,and then administered orally or parenterally. When these agents areseparately formulated into different preparations, these preparationsmay be administered to a subject after mixing together by using diluentjust prior to use. Alternatively, these preparations may separately beadministered to the subject simultaneously or with a certain timeinterval. A kit product for mixing separate preparations using diluentand the like just prior to use for administration (e.g., a kit forinjection which contains two or more ampoules each containing adifferent powdery drug and a diluent for mixing the drugs just prior touse) as well as a kit product for administering separate preparations toa subject simultaneously or separately with a certain time interval(e.g., a kit for administering two or more types of separate tables to asubject simultaneously or separately with a certain time intervalwherein tablets each containing a different drug are packed in the samebag or different bags, and a column is provided on the bag in which atime interval for drug administration can be written) are encompassed bythe pharmaceutical compositions of the present invention.

Specific examples of other therapeutic agents which can be used incombination with compound having GPR 14 antagonizing activity or a saltthereof according to the present invention include:

drugs for treating hypertension such as diuretic [e.g., furosemide(Lasix), bumetanide (Lunetoron) or azosemide (Diart), etc.],antihypertensive drug [e.g., ACE inhibitor such as enalapril maleate(Renivace) or delapril hydrochloride, etc.] and Ca antagonist(manidipine or amlodipine), or •- or •-receptor blocker, etc.] etc.;

drugs for treating chronic heart failure such as cardiotonic drug [e.g.,cardiotonic glycoside (e.g., digoxin), •-receptor stimulator(catecholamine preparation such as denopamine or dobutamine), PDEinhibitor, etc.], diuretic [e.g., furosemide (Lasix) or spironolactone(Aldactone), etc.], ACE inhibitor [e.g., enalapril maleate (Renivace),etc.], Ca antagonist [e.g., amlodipine, etc.], •-receptor blocker, etc.;

antiarrhythmic drugs such as disopyramide, lidocaine, quinidine sulfate,flecainide acetate, mexiletine hydrochloride, amiodarone hydrochloride,as well as •-blocker, Ca antagonist, etc.;

drugs for preventing and/or treating thrombogenesis: coagulationinhibitor [e.g., heparin sodium, heparin calcium, warfarin calcium(warfarin), blood coagulation factor Xa inhibitor and drugs capable ofbalancing coagulation fibrinolytic system], thrombolytic agent [e.g.,tPA, urokinase, prourokinase, etc.], antiplatelet drug [e.g., aspirin,sulfinpyrazolo (Anturan), dipyridamole (Persantin), ticlopidine(Panaldine), cilostazol (Pletaal) and GP IIb/IIIa antagonist (ReoPro),etc.], etc.;

coronary vasodilators such as nifedipine, diltiazem, nicorandil, nitriteagent, etc.;

cardioplegic drugs such as opener for cardiac ATP-K, Na—H exchangeinhibitor, endothelin antagonist, urotensin antagonist, etc; and thelike.

Further, compound (I) of the present invention has somatostatin acceptorregulatory activity (somatostatin acceptor agonistic and/or antagonisticactivity). That is, compound (I) acts through somatostatin-relatingvarious intracellular information transmission systems. Examples of the“intracellular information transmission systems” include intracellularinformation transmission systems involving transcription factors such asadenylate cyclase, the K⁺ channel, the Ca²⁺ channel, protein dephosphateoxidation, the phospholipase C/inositol3-phosphoric acid producingsystem, MAP kinase, the Na⁺/H⁺ exchange system, phospholipase A2, andNF-•B etc., and the like. Further, compound (I) also regulates direct orindirect cell growth suppression activity or apoptosis activityinvolving somatostatin.

Furthermore, compound (I) has low in toxicity and acts on eachsomatostatin acceptor (for example, antagonistic or agonistic activity)of a mammal (e.g., human, cow, horse, dog, cat, monkey, mouse, rat,etc., particularly human) to accelerate or suppress the productionand/or secretion of a variety of hormones, growth factors,physiologically active substances, etc.

Examples of the “hormones” include growth hormone (GH), growth hormonerelieving hormone (GHRH), thyroid-stimulating hormone(TSH), prolactin,insulin, glucagon, etc. Examples of the “growth factors” includeinsulin-like growth factor-1 (IGF-1), vascular endothelial growth factor(VEGF), etc. Examples of the “physiologically active substances” includeinterleukins such as vasoactive intestinal polypeptide (VIP), gastrin,glucagon-like peptide-1, amylin, substance-P, CCK (cholecystokinin),amylase, interleukin-6 (IL-6), interleukin-1 (IL-1), cytokines such asTNF-•, cardiotropin, etc.

Therefore, compound (I) is safe and useful for abnormality of theabove-described intracellular information transmission systems (e.g.,diseases along with excessive acceleration or suppression, etc.),diseases associated with abnormality of cell growth control, diseasesalong with the abnormality of the production and/or secretion ofhormones, growth factors physiologically active substances, etc.,acceleration of growth, immunity, stomach and intestines, metabolismfunction, etc.

For example, compound (I) is useful (1) as a therapeutic drug for tumorsof acromegaly, TSH producing tumor, non-secretion (non-functionality)hypophysoma, dystopic ACTH (adrenocorticotopin) producing tumor,medullary thyroid cancer, VIP producing tumor, glucagon producing tumor,gastorin producing tumor, insulinoma, carcinoid, etc.; (2) as atherapeutic drug for insulin dependent or independent diabete or avariety of diseases associated with these diabetes, i.e., diabetescomplications (e.g., diabetic retinosis, diabetic nephropathy, diabeticneuropathy, dawn phenomenon, orthostatic hypotension, etc.); (3) as atherapeutic drug for obesity and polyphagia caused by improvement ofhyperinsulinemia or suppression of appetite, etc.; (4) as a therapeuticdrug for acute pancreatitis, chronic pancreatitis, pancreas/intestinestomy, hemorrhagic tumors, peptic tumors, gastritis, chlorhydria,regurgitant esophagitis, etc.; (5) as a improving drug for a variety ofsymptoms in association with Helicobacter pylori infection (e.g.,suppressing agent for gastrin secretion acceleration, etc.); (6) as asecretion suppressing drug for amylase associated with endoscopycholangiopancreatography and further a therapeutic drug for theprognosis of the pancreas surgery; (7) as a therapeutic drug fordecrease in absorption ability of small intestines, diarrhea due tosecretion acceleration or the abnormality of movement ability ofdigestive tracts (e.g., short bowel syndromes, etc.), diarrhea caused bya drug for use in cancer chemotherapy, diarrhea due to congenital smallintestine atrophy, diarrhea due to neuroendocrine tumors such as VIPproducing tumors, diarrhea due to AIDS, diarrhea due to anti-host graftreaction associated with marrow transplantation, etc., diarrhea due todiabetes, diarrhea due to coeliac plexus block, diarrhea due to systemicscelosis, diarrhea due to eosinophilia, etc.; (8) as a therapeutic drugfor damping complex, hypersensitive colitis, Crohn's disease,inflammatory enteropathy, etc.; (9) as a therapeutic drug for tumors orcancer (e.g., thyroid cancer, colon cancer, mastocarcinoma, prostatecancer, small cell lung carcinoma, non-small cell lung carcinomapancreas cancer, stomach cancer, cholangioma, liver cancer, bladdercancer, oophoron cancer, melanoma, osteosarcoma, chondrosarcoma,malignant pheochromocytoma, neuroblastoma, encephalophyma, thymoma,kidney cancer, etc.), leukemia (e.g., leukemia of basiphilic leucocyteand chronic lymphemia, chronic myelogenic leukemia, Hodgkin's disease,non-Hodgkin lymphoma, etc.), etc., the therapeutic drug being usablesingly or in combination with other carcinostatic drugs (e.g.,tamoxifen, LHRH agonist, LHRH antagonist, interferon •, •, and •,interleukin-2, etc.); (10) as a preventive or therapeutic drug forhypertrophic cardiomyopathy, arteriosclerosis, the valvular disease ofthe heart, myocardial infarction (particularly, cardiac infarction afterthe formation surgery for the transdermal per tubam coronary artery),and re-vascularization; (11) as a therapeutic drug for esophageal veincancer bleeding, hepatocirrhosis, peripheral vasculopathy diseases; (12)as a therapeutic drug for diseases based on the control action onsecretion of physiologically active substances (e.g., substance P,tachykinin, cytokine, etc.) acting on the immune system, for example,diseases in association with systemic or local inflammation (e.g.,polyarteritis, rheumatoid arthritis, psoriatic, sunburn, eczema, allergy(e.g., asthma, atopic dermatitis, allergic rhinitis, etc.), etc.); (13)as a therapeutic drug for diseases such as, for example, dementia (e.g.,Alzheimer's disease, Alzheimer type senescense dementia, vascularmultiple dementia, etc.), schizophrenia, epilepsia, ademonia, generalanxiety disorder, sleep disorder, multiple sclerosis, etc., which affectthe production and secretion of nerve controlling factors; (14) as atherapeutic drug for eye diseases (e.g., glaucoma, etc.); (15) as apreventive or therapeutic drug for acute bacteria meningitis, acutevirus cerebritis, the adult respiration pressing syndromes, bacteriapneumonia, severe systemic fungus infectious diseases, tuberculosis,spine damage, fracture, liver failure, pneumonia, alcoholic hepatitis,hepatitis A, hepatitis B, hepatitis C, AIDS contagious diseases, humanpapilloma virus infectious diseases, influenza infectious disease,cancer metastasis, multiple myeloma, chondrification disease,osteoporosis, bone Behchet's disease, nephritis, renal failure,septicemia, septicemia shock, hypercalcemia, hypercholesterolemia,hyperglyceridemia, hyperlipemia, systemic lupus erythematosus, transientbrain ischemic attack, alcoholic hepatitis, etc.; (16) for treatment oforgan transplant, burn, vulnus, alopecia, etc.; (17) as a lenitive forsuppressing or relieving chronic or acute aches (e.g., aches aftersurgery, inflammatory aches, teeth aches, and aches associated with bonediseases (e.g., arthritis, rheumatism, osteoporosis, etc.)).Furthermore, the compound (I) is usable for (18) imaging of a tumorhaving a somatostatin acceptor formed by introducing a radioactivesubstance (e.g., ¹²³I, ¹²⁵I, ¹¹¹In, etc.) into the compound (I) directlyor via an appropriate spacer, or (19) targeting for a tumor having asomatostatin acceptor formed by introducing a carcinostatic into thecompound (I) directly or via an appropriate spacer.

Also, somatostatin associates with, for example, secretion of growthhormones (particularly, SSTR2), and compound (I) can have the sameeffect or use as that of growth hormone itself when it is used directlyor for the purpose of promoting secretion of growth hormone. Therefore,compound (I) can be used for prevention or treatment of diseases orsymptoms attributable to the shortage of growth hormone or IGF-1.

Examples of the “prevention or treatment of diseases or symptomsattributable to the shortage of growth hormone or IGF-1” includetreatment of insulin dependent (I type) or independent (II type)diabetes, or a variety of diseases associated with diabetes, i.e.,diabetes complications (e.g., diabetic retinitis, diabetic nephrosis,diabetic neuropathy, dawn phenomenon, orthostatic hypotension, etc.);prevention of the catabolic side-effect of glucocorticoid, prevention ortreatment of osteoporosis, stimulation of the immune system (increaseand enhancement of blood cells such as lymph cells, enhancement ofantibacterial action or anti-virus action), promotion of healing of burnor vulnus, acceleration of fracture curing, treatment of acute orchronic kidney diseases, treatment or improvement of diseases orsymptoms (short height, growth delay) associated with growth hormoneshortage in adulthood or infancy, treatment of obesity, promotion ofrecovery after surgery, improvement of growth delay associated withPrader-Willi syndromes or Turner syndromes, treatment of intrauterinegrowth delay or bone formation abnormality, treatment of peripheralnerve diseases, treatment of Noonan syndromes, schizophrenia, ademonia,etc., treatment or prevention of nerve degeneration diseases such asAlzheimer's disease and Parkinson's disease, treatment of lung failureor ventilation dependency disease, treatment of absorption failuresyndromes, improvement of cachexia or protein loss due to cancer, AIDS,etc., promotion of weight increase and protein attachment for patientduring total parenteral nutrition (TPN), treatment of hyperinsulinism,promotion of ovulation induction, improvement of climacteric disorders,improvement of senile constitution, etc.

In addition, with mammals like cattle as well, the compound is usefulfor promotion of growth, increase of milk production, enhancement ofanti-bacterial or anti-viral action by stimulation of the immune system,stimulation of wool growth in sheep, etc.

Compound (I) may be used with various preparations for combination use.

For example, in the treatment of osteoporosis, it can also be used incombination with other osteoporosis treatment preparations (e.g.,bisphosphonate drugs, vitamin D preparations, calcitonin preparations,PTH preparations, ostein, etc.).

In the treatment of diabetes or associated diseases thereof, thecompound is usable in combination with other diabetes treating drugs(e.g., troglitazone, pioglytazone, or hydrochlorides thereof,rosiglitazone or thiazolidinedione drugs such as maleate thereof;glucagon antagonists; ●-glucosidase inhibitors such as acarbose, andvoglibose; insulin preparations; insulin secretion promoting agents suchas sulfonylurea agents or sulfonamide agents (e.g., glibenclamide,tolbutamide, glyclopyramide, acetohexamide, tolazamide, gliclazide,glybuzole, glymepyride, etc.), lepaglynide, natheglynide, andmichiglynide; biguanide agents such as metformin and buformin, etc.).

Further, the compound can also be used in combination with otherhormones that promote growth hormone secretion (e.g., GHRH), GH, orIGF-1.

In the improvement of climacterium disorders, the compound is usable incombination with, for example, hormone supplementation therapy (e.g.,therapies by means of estrogen drugs, raloxifene, and tamoxifen).

For the purpose of accelerating the immune system, the compound can beused in combination with cytokines or agents for enhancing cytokineactions as well.

When compound (I) of the present invention is used for adult acromegaliapatients, diabetes complications, inveterate diarrhea, diabetes, orobesity, daily dose thereof may depend on various factors such as thecondition and weight of the patient to be treated and administrationmanner. For oral administration, the compound may be administered at anamount of about 0.05 to 1000 mg, preferably about 10 to 150 mg as anactive component [(e.g., compound (I)] per an adult (50 kg).

Although the present invention will be described in more detail byreferring to Experimental Examples, Preparation Examples, ReferenceExample and Synthesis Examples, these examples are provided toillustrate the invention but not to limit its scope.

Brief description of SEQ ID NOS used herein will be provided below:

[SEQ ID NO: 1]

A synthetic DNA used for screening cDNA encoding human GPR14 protein.

[SEQ ID NO: 2]

A synthetic DNA used for screening cDNA encoding human GPR14 protein.

[SEQ ID NO: 3]

An entire nucleotide sequence of cDNA encoding human GPR14 protein towhich nucleotide sequences recognized by restriction enzymes Sal I andSpe I have been added at the 5′- and 3′-termini, respectively.

[SEQ ID NO: 4]

An amino acid sequence of human GPR14 protein confirmed in ReferenceExample 2.

[SEQ ID NO: 5]

A nucleotide sequence of DNA oligomer S5-1 based on the nucleotidesequence of human•SSTR cDNA synthesized in Reference Example 4.

[SEQ ID NO: 6]

A nucleotide sequence of DNA oligomer S5-2 based on the nucleotidesequence of human•SSTR cDNA synthesized in Reference Example 4.

REFERENCE EXAMPLE 1 Amplifying cDNA for Human GPR14 Receptor by PCRMethod Using Human Skeletal Muscle-Derived cDNA

PCR amplification was performed by using cDNA derived from humanskeletal muscle (Clontech) as a template and two synthetic DNA primers(SEQ ID NOS: 1 and 2). The synthetic DNA primers were designed so thatthe gene in the region which is to be translated into receptor proteinwould be amplified, and such that nucleotide sequences which may berecognized by restriction enzymes Sal I and Spe I were added at the 5′-and 3′-termini of the gene, respectively. Reaction solution included 2.5μl of cDNA template, synthetic DNA primers (0.2 μM each), 0.2 mM dNTPs,1 μl of Advantage 2 polymerase mix (Clontech) and the buffer appended tothe enzyme (total reaction volume of 50 μl). Thermocycler (Perkin-ElmerCorp.) was used for amplification. The amplification cycle consisted ofheating at 95° C. for 60 seconds, followed by 5 rounds of 95° C. for 30seconds and 72° C. for 3 minutes, 5 rounds of 95° C. for 30 seconds and70° C. for 3 minutes, and then 20 rounds of 95° C. for 30 seconds and68° C. for 3 minutes, and finally heating at 68° C. for 3 minutes. Theresultant PCR amplification products were confirmed by purification byelectrophoresis on a 0.8% agarose gel followed by staining with ethidiumbromide.

REFERENCE EXAMPLE 2 Subcloning of PCR Product into Plasmid Vector andConfirming Amplified cDNA by Reading the Nucleotide Sequence of cDNAInsert

PCR reaction products obtained in Reference Example 1 were separated ona 0.8% low-melting agarose gel, a gel containing bands was excised usinga razor, and DNA was collected using GENECLEAN SPIN (BIO 101, Inc.).According to the prescription included in Eukaryotic TOPO™ TA Cloningkit (Invitrogen), the collected DNA was cloned into a plasmid vector forexpression in animal cells, pcDNA3.1/V5/His, to construct a plasmid forprotein expression, pcDNA3.1-hGPR14 which was then introduced intoEscherichia coli DH5α competent cells (Toyobo Co., Ltd.) fortransformation. Then, clone which contained cDNA insert fragment wasselected on an ampicillin-containing LB agar medium, and separated usinga sterilized toothpick to obtain transformant E. coliDH5α/pcDNA3.1-hGPR14. Each clone was cultured overnight on anampicillin-containing LB medium, and Quiawell 8 Ultra Plasmid kit(Qiagen) was used to prepare plasmid DNA. Portion of DNA prepared wasdigested with restriction enzyme Sal I, and the size and direction ofreceptor cDNA fragment inserted were determined. The sequences ofnucleotides were determined by using DyeDeoxy Terminator Cycle SequenceKit (Perkin-Elmer Corp.) and then reading in a fluorescence automaticsequencer. The sequence of clone obtained was analyzed and confirmed tobe consistent with a genetic sequence comprising the sequence of humanGPR14 gene, of which entire sequence has been reported (EP 0 859 052A1), and Sal I and Spe I recognition sequences added to the 5′- and3′-termini of the sequence, respectively (SEQ ID NOS: 3 and 4). Itshould be noted that although the 1133rd base in the sequence of humanGPR14 gene (SEQ ID NO: 3) was identified as C in the report (EP 0 859052 A1) while it was identified as G in the present Example though theamino acids which would be translated from these sequences may be thesame.

REFERENCE EXAMPLE 3 Preparing Human GPR14-Expressing CHO Cell

After the transformant E. coli DH5α/pcDNA3.1-hGPR14 prepared inReference Example 2 was cultured, plasmid DNA for pcDNA3.1-hGPR14 wasprepared by using Plasmid Midi Kit (Qiagen). The plasmid DNA wasintroduced into CHO dhfr⁻ cells using CellPhect Transfection Kit(Amersham Pharmacia Biotech) according to the protocol appended thereto.10 μg of DNA was co-precipitated with calcium phosphate to prepare asuspension which was then added to a 10 cm petri dish on which 5×10⁵ or1×10⁶ CHO dhfr⁻ cells had previously been inoculated 24 hours beforethen. Cells were cultured in a MEMα medium containing 10% fetal bovineserum for one day, subcultured, and cultured in a selection medium, aMEMA medium containing 0.4 mg/ml G418 (GIBCO BRL) and 10% dialysis fetalbovine serum. Colonies of transformed cells (CHO/hGPR14), which werehuman GPR14-expessing CHO cells growing in the selection medium, wereselected.

EXPERIMENTAL EXAMPLE 1 Preparing Human GPR14-Expressing Cell Fraction

To 1×10⁸ CHO/GPR14 cells were added 10 ml of homogenate buffer (10 mMNaHCO₃, 5 mM EDTA, 0.5 mM PMSF, 1 μg/ml pepstatin, 4 μg/ml E64, 20 μg/mlleupeptin), and disrupted using Polytron (12,000 rpm, 1 minute). Celldebris solution was centrifuged at 1,000 g for 15 minutes to obtain asupernatant. The supernatant was then ultra-sonicated (in Beckman type30 rotor, 30,000 rpm, 1 hour), and the resultant precipitant wascollected as human GPR14-expressing CHO cell fraction.

EXPERIMENTAL EXAMPLE 2 Preparing Isotope-Labeled Human Urotensin II

Isotope-labeled human urotensin II to be used in experiments for testinginhibition of binding was prepared as described below. 5 μg of humanurotensin II (available from Peptide Institute, Inc.) was dissolved in25 μl of 0.4 M sodium acetate (pH 5.6). To the solution was added 200 ngof lactoperoxidase (Wako Pure Chemical Industries, Ltd.) followed by 1mCi [¹²⁵I]-sodium iodide (Amersham Pharmacia Biotech) and 200 ng ofhydrogen peroxide (10 μl). The solution was left to stand at roomtemperature for 10 minutes, another 200 ng of hydrogen peroxide (10 μl)was added thereto and then the solution was left to stand for 10minutes. The mixture was then purified by HPLC using TSKgel ODS-80T_(s)column (4.6 mm×25 cm, Toso Co., Ltd.) to obtain [¹²⁵I]-labeled humanurotensin II.

EXPERIMENTAL EXAMPLE 3 Experiment for Testing the Ability of TestCompound to Inhibit Binding of Urotensin II to GPR14 Using HumanGPR14-Expressing Cell Fraction and Isotope-Labeled Urotensin II

Human GPR14-expressing CHO cell fraction was diluted in a membranediluting buffer (20 mM phosphate buffer (pH 7.3), 150 mM NaCl, 5 mMMgCl₂, 0.1% BSA, 0.05% CHAPS, 0.5 mM PMSF, 0.1 μg/ml Pepstatin, 20 μg/mlLeupeptin, 4 μg/ml E-64) to prepare a solution of cell membrane fraction(protein concentration: 3 μg/ml) for assay. The membrane fractionsolution for assay was dispensed in 96-well microplates (85 μl each)which were left for stand for reaction at 25° C. for 3 hours afteradding: 10 μl of membrane diluting buffer containing 1 nM [¹²⁵I]-labeledhuman urotensin II and 5 μl of di-methylsulfoxide diluted 5-times (byvolume) in membrane diluting buffer for examining the total binding; 10μl of membrane diluting buffer containing 1 nM [¹²⁵I]-labeled humanurotensin II and 5 μl of 20% dimethylsulfoxide-containing membranediluting buffer containing 20 μM human urotensin II withoutisotope-labeling for examining non-specific binding; and 5 μl of asolution of test compound in di-methylsulfoxide diluted 5-times (byvolume) in membrane diluting buffer and 10 μl of membrane dilutingsolution containing 1 nM [¹²⁵I]-labeled-human urotensin II for testingthe ability of test compounds to inhibit binding. The mixture solutionwas filtrated through a filter plate (GF/C, Watman). Next, the filterwas washed three times with membrane diluting buffer (0.2 ml), addedwith 20 μl of Microscinti 20 (Packard), and determined for radioactivityin Topcount (Packard). Specific-binding is calculated by subtractingnon-specific binding from the total binding. The ability of testcompound to inhibit binding of urotensin II to human GPR14 isrepresented by the ratio of [(total binding)−(the radio activity of thecell fraction to which test compound was added)] vs [specific binding].Concentrations of test compounds at which the compounds showed 50%inhibition of human GPR14 binding activity are shown.

Results are shown in Table 1.

TABLE 1 Test compound Inhibitory concentration Compound of Example 4 10nM Compound of Example 6 13 nM

EXPERIMENTAL EXAMPLE 4 Change in Calcium Concentration in HumanGPR14-Expressing CHO Cell Caused by Test Compound

GPR14-expressing CHO cells were inoculated on a 96-well plate at 1×10⁴cell/well, cultured for 48 hours, and then washed with 0.1 ml of HBSScontaining 20 mM HEPES(pH 7.4), 1% FCS and 1% penicillin-streptomycin(hereinafter referred to as “wash buffer”). Next, 100 μl of another washbuffer containing 4 μM Fluo3, 0.04% pluronic acid and 2.5 mM probenicid(hereinafter referred to as “reaction buffer”) was added thereto forreaction at 37° C. for 1 hour. The reaction buffer was then removed andthe plate was washed three times with 0.2 ml of wash buffer. Then, 90 μlof wash buffer and 10 μl of a solution of test compound indimethylsulfoxide diluted 10 times (by volume) in membrane dilutingbuffer were added for agonist activity assay, while, for antagonistactivity assay, furthermore 10 μl of 10 nM urotensin II was additionallyadded to determine change in intracellular calcium concentration inFLIPR (Japan Molecular Device). The test compound (compound of Example71) inhibited urotensin II-induced increase in intracellular calciumconcentration.

A vasoactive agent (e.g., an agent for preventing and/or treatingmyocardial infarction, heart failure and the like) comprising as anactive component the compound having GPR 14 antagonistic activity of thepresent invention can be produced, for example, as follows.

PREPARATION EXAMPLES

1. Capsules (1) Compound obtained in Example 1  40 mg (2) Lactose  70 mg(3) Microcrystalline cellulose  9 mg (4) Magnesium stearate  1 mg 1capsule 120 mg

(1), (2), (3) and ½ of (4) are mixed and then granulated. The remainderof (4) is added to the granules, and the whole is sealed in a gelatincapsule.

2. Tablets (1) Compound obtained in Example 1  40 mg (2) Lactose  58 mg(3) Corn starch  18 mg (4) Microcrystalline cellulose  3.5 mg (5)Magnesium stearate  0.5 mg 1 tablet 120 mg

(1), (2), (3), ⅔ of (4) and ½ of (5) are mixed and then granulated. Theremainders of (4) and (5) are added to the granules, and the whole ispressure-molded into a tablet.

SYNTHESIS EXAMPLES

In the following Examples, measurement in HPLC was carried under thefollowing condition A or B:

Measuring instrument: Shimadzu Corporation LC-10 Avp system

Condition A

Column: CAPCELL PAK C18UG120, S-3 •m, 2.0×50 mm

Solvent: Solution A, 0.1% aqueous trifluoroacetic acid;

Solution B, 0.1% trifluoroacetic acid in acetonitrile

Gradient cycle: 0.00 min. (Solution A/Solution B=90/10), 4.00 min.(Solution A/Solution B=5/95), 5.50 min. (Solution A/Solution B=5/95),5.51 min. (Solution A/Solution B=90/10), 8.00 min. (Solution A/SolutionB=90/10)

Injection volume: 2 •l; flow rate: 0.5 ml/min.; detection method: UV 220nm

Condition B

Column: CAPCELL PAK C18UG120, S-3 •m, 2.0×35 mm

Solvent: Solution A, 0.1% aqueous trifluoroacetic acid;

Solution B, 0.1% trifluoroacetic acid in acetonitrile

Gradient cycle: 0.00 min. (Solution A/Solution B=90/10), 2.00 min.(Solution A/Solution B=5/95), 2.75 min. (Solution A/Solution B=5/95),2.76 min. (Solution A/Solution B=90/10), 3.60 min. (Solution A/SolutionB=90/10)

Injection volume: 5 •l; flow rate: 1.0 ml/min.; detection method: UV 220nm

In the Examples below, measurement by mass spectrometry (MS) was carriedout under the following conditions.

Measuring instrument: Micromass Ltd. Platform II

Ionization method: Atmospheric Pressure Chemical Ionization (APCI) orElectron Spray Ionization (ESI)

In the following Examples, purification by preparative HPLC was carriedout under the following conditions.

Instrument: Gilson Ltd. High-Throughput Purification System

Column: YMC CombiPrep ODS-A, S-5 •m, 50×20 mm

Solvent: Solution A, 0.1% aqueous trifluoroacetic acid;

Solution B, 0.1% trifluoroacetic acid in acetonitrile

Gradient cycle: 0.00 min. (Solution A/Solution B=90/10), 1.00 min.(Solution A/Solution B=90/10), 4.20 min. (Solution A/Solution B=10/90),5.40 min. (Solution A/Solution B=10/90), 5.50 min. (Solution A/SolutionB=90/10), 5.60 min. (Solution A/Solution B=90/10)Flow rate: 25 ml/min.; detection method: UV 220 nm

EXAMPLE 13′-{({2-[4-(Aminosulfonyl)phenyl]ethyl}[(E)-3-phenyl-2-propenoyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamide 1)3-Bromo-N-[2-(1-pyrrolidinyl)ethyl]phenylcarboxamide

1-(2-Aminoethyl)pyrrolidine (4.34 g), diethyl cyanophosphate (5.57 ml)and triethylamine (10.4 ml) were added to a solution of 3-bromobenzoicacid (5.00 g) in N,N-dimethylformamide (DMF; 60 ml), and the mixture wasstirred at room temperature for 16 hours. The reaction mixture wasdiluted with water and then extracted with diethyl ether. The extractwas dried over anhydrous magnesium sulfate, and then the solvent wasevaporated under reduced pressure. The residues were crystallized fromhexane to give the title compound (6.31 g).

¹H-NMR (CDCl₃) •: 1.70–1.90 (4H, m), 2.50–2.60 (4H, m), 2.70 (2H, t,J=6.0 Hz), 3.45–3.60 (2H, m), 6.86 (1H, s), 7.30 (1H, t, J=8.0 Hz), 7.60(1H, dm, J=8.0 Hz), 7.70 (1H, dm, 8.0 Hz), 7.93 (1H, t, J=1.6 Hz).

2) 3′-Formyl-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamide

Palladium tetrakistriphenyl phosphine (735 mg) and 2 M aqueous sodiumcarbonate (21.2 ml) were added to a solution of3-bromo-N-[2-(1-pyrrolidinyl)ethyl]phenylcarboxamide (6.31 g) in toluene(50 ml), and then a solution of 3-formylphenylboric acid (3.49 g) inethanol (15 ml) was added thereto, and the mixture was stirred at 90° C.for 15 hours. The reaction solution was diluted with water and thenextracted with diethyl ether. The extract was washed with brine and thendried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, whereby the title compound (6.83 g) was obtained.

¹H-NMR (CDCl₃) •: 1.95–2.35 (4H, m), 2.95 (2H, m), 3.30–3.50 (2H, m),3.80–3.40 (4H, m), 7.40–7.60 (2H, m), 7.76 (1H, dm, J=8.0 Hz), 7.85 (1H,dm, J=8.0 Hz), 8.00 (1H, dm, 8.0 Hz), 8.09 (1H, dm, J=8.0 Hz), 8.25 (1H,bs), 8.40 (1H, bs), 8.41 (1H, m), 10.10 (1H, s).

3.3′-[{2-[4-(Aminosulfonyl)phenyl]ethyl}aminomethyl]-N-[2-(1-pyrrolidinyl)ethyl]-[1,1′-biphenyl]-3-carboxamide

4-(2-Aminoethyl)benzene sulfonamide (2.37 g) and molecular sieves 3A(4.0 g) were added to a solution of3′-formyl-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamide (3.81g) in methanol (50 ml), and the mixture was stirred at room temperaturefor 1.5 hours. After the reaction mixture was diluted withtetrahydrofuran (THF), the molecular sieves were filtered off, and thefiltrate was concentrated under reduced pressure. The residues weredissolved in a mixed solvent (100 ml) of methanol-THF (1:1), and sodiumborohydride (0.89 g) was added thereto. The reaction mixture was stirredat room temperature for 5 hours, and then the solvent was evaporatedunder reduced pressure. The residues were diluted with water andextracted with ethyl acetate. The extract was washed with brine and thendried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residues were crystallized from hexane,whereby the title compound (3.71 g) was obtained.

¹H-NMR (CDCl₃) •: 1.75–1.85 (4H, m), 2.55–2.65 (4H, m), 2.78 (2H, t,J=6.0 Hz), 2.85–3.00 (4H, m), 3.60–3.65 (2H, m), 3.87 (2H, s), 7.05–7.15(1H, m), 7.20–7.60 (6H, m), 7.65–7.85 3H, m), 7.84 (2H, d, J=8.4 Hz),8.05 (1H, s).

4)3′-{({2-[4-(Aminosulfonyl)phenyl]ethyl}[(E)-3-phenyl-2-propenoyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamide

3′-[{2-[4-(Aminosulfonyl)phenyl]ethyl}aminomethyl]-N-[2-(1-pyrrolidinyl)ethyl]-[1,1′-biphenyl]-3-carboxamide(506 mg), trans-cinnamic acid (163 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl;211 mg) and 1-hydroxybenzotriazole (HOBT; 149 mg) were dissolved in amixed solvent of dichloromethane (15 ml) and DMF (7 ml), and the mixturewas stirred at room temperature for 18 hours. The solvent was evaporatedunder reduced pressure, and water was added to the residues which werethen extracted with ethyl acetate. The extract was washed with brine anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residues were purified by silica gel columnchromatography (dichloromethane/methanol=98/2), whereby the titlecompound (284 mg) was obtained.

¹H-NMR (CDCl₃) •: 1.73 (4H, m), 2.52 (4H, m), 2.69 (2H, t, J=6.0 Hz),2.85–3.00 (2H, m), 3.50–3.60 (2H, m), 3.66 (2H, t, J=7.0 Hz), 4.60(2H,s), 6.57 (1H, d, J=15.6 Hz), 6.85 (1H, d, J=15.6 Hz), 7.10–7.90(16H, m), 8.05 (1H, s).

MS (APCI+): 637 (M+H)

EXAMPLE 23′-{-({2-[4-(Aminosulfonyl)phenyl]ethyl}[(E)-3-phenyl-2-propenoyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidehydrochloride

3′-{({2-[4-(Aminosulfonyl)phenyl]ethyl}[(E)-3-phenyl-2-propenoyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamide(200 mg) was treated with 4 N hydrogen chloride in ethyl acetate to givethe title compound (198 mg).

¹H-NMR (DMSO-d₆) •: 1.80–2.10 (4H, m), 2.90–3.10 (4H, m), 3.30–3.50 (2H,m), 3.55–3.90 (6H, m), 4.73 (2H,s), 7.05–8.00 (18H, m), 8.25 (1H, s),9.03 (1H, m).

Elemental analysis (molecular formula C₃₇H₄₀N₄O₄S.HCl.1.5H₂O):

Theoretical: C: 63.46; H: 6.33; N: 8.00; Cl: 5.08

Found: C: 63.65; H: 6.51; N: 7.86; Cl: 5.25

EXAMPLE 33′-{({2-[4-(Aminosulfonyl)phenyl]ethyl}[4-phenylbutanoyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamide

The title compound (277 mg) was obtained in the same manner as inExample 1.

¹H-NMR (DMSO-d₆) •: 1.75–1.85 (8H, m), 2.20–2.40 (2H, m), 2.45–2.60 (2H,m), 2.60–2.95 (4H, m), 3.20–3.60 (6H, m), 4.62 (2H,s), 7.05–7.95 (18H,m), 8.13 (1H, s), 8.71 (1H, m).

MS (ESI+): 653 (M+H)

EXAMPLE 43′-{({2-[4-(Aminosulfonyl)phenyl]ethyl}[4-phenylbutanoyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidehydrochloride

The title compound (185 mg) was obtained in the same manner as inExample 2.

¹H-NMR (DMSO-d₆) •: 1.75–2.10 (8H, m), 2.25–2.45 (2H, m), 2.45–2.60 (2H,m), 2.80–2.90 (2H, m), 2.95–3.10 (2H, m), 3.20–3.50 (2H, m), 3.50–3.75(4H, m), 4.61 (2H,s), 7.05–8.00 (18H, m), 8.23 (1H, s), 9.02 (1H, m).

Elemental analysis (molecular formula C₃₈H₄₄N₄O₄S.HCl.H₂O)

Theoretical: C: 64.53; H: 6.70; N: 7.92; Cl: 5.01

Found: C: 64.39; H: 6.82; N: 7.86; Cl: 5.20

EXAMPLE 53′-{({2-[4-(Aminosulfonyl)phenyl]ethyl}[(benzyloxy)acetyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamide

Pyridine (0.16 ml) and benzyloxyacetyl chloride (0.16 ml) were added toa solution of3′-[{2-[4-(aminosulfonyl)phenyl]ethyl}aminomethyl]-N-[2-(1-pyrrolidinyl)ethyl]-[1,1′-biphenyl]-3-carboxamide(506 mg) in DMF (10 ml). The reaction mixture was stirred at roomtemperature for 16 hours, then diluted with water and extracted withethyl acetate. The extract was washed with brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residues were purified by silica gel columnchromatography (dichloromethane/methanol=98/2), whereby the titlecompound (257 mg) was obtained.

¹H-NMR (CDCl₃) •: 1.74 (4H, m), 2.60–2.80 (4H, m), 2.88 (2H, m),3.20–3.40 (8H, m), 4.17 (2H,s), 4.47 (2H, s), 4.62 (2H, s), 6.57 (1H, d,J=15.6 Hz), 7.20–7.90 (18H, m), 8.11 (1H, s), 8.65 (1H, m).

MS (ESI+): 655 (M+H)

EXAMPLE 63′-{({2-[4-(Aminosulfonyl)phenyl]ethyl}[(benzyloxy)acetyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidehydrochloride

The title compound (155 mg) was obtained in the same manner as inExample 2.

¹H-NMR (DMSO-d₆) •: 1.80–2.10 (4H, m), 3.80–3.15 (6H, m), 3.20–3.50 (2H,m), 3.60–3.75 (4H, m), 4.19 (2H, s), 4.48 (2H, s), 4.62 (2H, s),7.20–7.90 (18H, m), 8.11 (1H, s), 8.65 (1H, m).

Elemental analysis (molecular formula C₃₇H₄₂N₄O₅S.HCl.1.5H₂O)

Theoretical: C: 61.87; H: 6.45; N: 7.80; Cl: 4.94

Found: C: 61.76; H: 6.31; N: 7.73; Cl: 5.25

EXAMPLE 7N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[[(E)-3-(4-bromophenyl)-2-propenoyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate 1) Methyl3′-[{(4-hydroxyphenetyl)imino}methyl][1,1′-biphenyl]-3-carboxylate

Tyramine (10.0 g) and molecular sieves 3A (40 g) were added to asolution of methyl 3′-formyl[1,1′-biphenyl]-3-carboxylate (10.0 g) inmethanol (200 ml), and the mixture was stirred at room temperature for 1hour. After the reaction mixture was diluted with tetrahydrofuran (THF),the molecular sieves were filtered off and the filtrate was concentratedunder reduced pressure, whereby the title compound (15.0 g) wasobtained.

¹H-NMR (CDCl₃) •: 2.94 (2H, t, J=7.0 Hz), 3.85 (2H, t, J=7.0 Hz), 3.94(3H, s), 6.76 (2H, d, J=8.4 Hz), 7.04 (2H, d, J=8.4 Hz).

2) Methyl 3′-[{(4-Wang resinphenethyl)imino}methyl][1,1′-biphenyl]-3-carboxylate

A solution of sodium methoxide in methanol (4.8 M; 8.7 ml) was added toa solution of methyl3′-[{(4-hydroxyphenethyl)imino}methyl][1,1′-biphenyl]-3-carboxylate(15.0 g) in DMF (300 ml), and after the mixture was stirred at roomtemperature for 1 hour, a suspension of Wang bromoresin (15.9 g) in DMF(200 ml) was added thereto. The reaction mixture was stirred at 80° C.for 17 hours and diluted with water, and the solvent was removed byfiltration. The resultant resin was washed with a mixed solvent ofDMF-water (1:1), DMF, THF and methanol in this order and dried at 50° C.under reduced pressure, whereby the title compound (19.9 g) wasobtained.

Magnetic Angle Spinning (MAS)—NMR (CDCl₃) •: 3.83 (methyl carboxylate),8.13 (imine)

IR (KBr): 1643 cm⁻¹

Amount of the compound carried on the resin: 0.83 mmol/g (elementalanalysis: calculated from 1.16% N)

3) Methyl 3′-[{(4-Wang resinphenetyl)amino}methyl][1,1′-biphenyl]-3-carboxylate

Sodium borohydride (1.87 g) was added to a mixture of methyl3′-[{(4-Wang resin phenethyl)imino}methyl][1,1′-biphenyl]-3-carboxylate(19.9 g) and a mixed solvent (400 ml) of methanol-THF (1:1), and themixture was stirred at room temperature for 18 hours. After the reactionsolution was diluted with water, the solvent was removed by filtration,and the resultant resin was washed with THF, a mixed solvent ofTHF-water (1:1), THF and methanol in this order and then dried at 50° C.under reduced pressure, to give the title compound (20.4 g).

MAS-NMR (CDCl₃) δ: 3.83 (methyl carboxylate)

4) 3′-[{(4-Wang resinphenethyl)amino}methyl][1,1′-biphenyl]-3-carboxylic acid

A mixture of methyl 3′-[{(4-Wang resinphenethyl)amino}methyl][1,1′-biphenyl]-3-carboxylate (20.0 g), 1 Naqueous sodium hydroxide (165 ml) and dioxane (330 ml) was stirred at80° C. for 62 hours. The solvent was removed by filtration, and theresultant resin was washed with THF, a mixed solvent of THF-acetic acid(1:1), THF and methanol in this order and then dried at 50° C. underreduced pressure, to give the title compound (19.5 g). The resultantresin (5 beads) was treated with trifluoroacetic acid-dichloromethane(1:1, 50 ml) to give3′-[{(4-hydroxyphenethyl)amino}methyl][1,1′-biphenyl]-3-carboxylic acidwhich was then analyzed in HPLC and measured by mass spectrometry.

HPLC analysis (condition A): purity 96% (retention time: 2.612 min.)

MS (APCI+): 348 (M+H)

5) N-{[4-(tert-Butoxycarbonylaminomethyl)cyclohexyl]methyl}-3′-{[(4-Wangresin phenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamide

tert-Butyl [4-(aminomethyl)cyclohexyl]methyl carbamate (61 mg),benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate(PyBOP; 133 mg) and N,N-diisopropylethylamine (DIEA; 44 ml) were addedto a suspension of 3′-[{(4-Wang resinphenethyl)amino}methyl][1,1′-biphenyl]-3-carboxylic acid (30 mg) in DMF(1.5 ml), and the mixture was stirred at room temperature for 38 hours.The solvent was removed by filtration, and the resultant resin waswashed with DMF, THF and methanol in this order and dried at 50° C.under reduced pressure to give the title compound (30 mg). The resultantresin (5 beads) was treated with trifluoroacetic acid-dichloromethane(1:1, 50 ml) to giveN-{[4-(aminomethyl)cyclohexyl]methyl}-3′-{[(4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidewhich was then analyzed in HPLC and measured by mass spectrometry.

HPLC analysis (condition A): purity 64% (retention time: 2.391 min.)

MS (APCI+): 472 (M+H)

6)N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[[(E)-3-(4-bromophenyl)-2-propenoyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

4-Bromocinnamic acid (29 mg), N,N′-diisopropylcarbodiimide (DIPCI; 24ml) and 1-hydroxy-7-benzotriazole (HOAT; 21 mg) were added to asuspension ofN-{[4-(tert-butoxycarbonylaminomethyl)cyclohexyl]methyl}-3′-{[(4-Wangresin phenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamide (30 mg) inDMF (2 ml), and the mixture was stirred at room temperature for 20hours. The solvent was removed by filtration, and the resultant resinwas washed with DMF, THF and methanol in this order and dried at 50° C.under reduced pressure. The resultant resin was treated withtrifluoroacetic acid-dichloromethane (1:1; 1 ml) and purified bypreparative HPLC to give the title compound (6.6 mg).

¹H-NMR (Acetone-d₆) •: 1.00–1.10 (2H, m), 1.50–1.70 (4H, m), 1.80–2.00(4H, m), 2.50–2.65 (2H, m), 2.80–2.95 (2H, m), 3.25–3.80 (4H, m), 4.79(2H,s), 6.76 (2H, d, J=8.4 Hz), 7.02 (1H, d, J=14.4 Hz), 7.08 (2H, d,J=8.4 Hz), 7.20–8.00 (13H, m), 8.13 (1H, s).

HPLC analysis (condition B): purity 100% (retention time: 1.730 min.)

MS (APCI+): 680 (M+H), 682

The following compounds were produced in the same manner as in Example7.

EXAMPLE 83′-{([4-Hydroxyphenethyl][(E)-3-phenyl-2-propenoyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.8 mg

HPLC analysis (condition A): purity 100% (retention time: 3.239 min.)

MS (APCI+): 574 (M+H)

EXAMPLE 93′-{([4-Hydroxyphenethyl][(benzyloxy)acetyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.7 mg

HPLC analysis (condition A): purity 98% (retention time: 3.166 min.)

MS (APCI+): 592 (M+H)

EXAMPLE 103′-{([4-Hydroxyphenethyl][4-phenylbutanoyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.8 mg

HPLC analysis (condition A): purity 100% (retention time: 3.330 min.)

MS (APCI+): 590 (M+H)

EXAMPLE 113′-{([4-Hydroxyphenethyl][3-(1H-indol-3-yl)propanoyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.1 mg

HPLC analysis (condition A): purity 97% (retention time: 3.225 min.)

MS (APCI+): 615 (M+H)

EXAMPLE 123′-{([4-Hydroxyphenethyl][2-(1H-indol-3-yl)acetyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.5 mg

HPLC analysis (condition A): purity 98% (retention time: 3.146 min.)

MS (APCI+): 601 (M+H)

EXAMPLE 133′-{([(E)-3-(2-Furyl)-2-propenoyl][4-hydroxyphenethyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.6 mg

HPLC analysis (condition A): purity 98% (retention time: 3.136 min.)

MS (APCI+): 564 (M+H)

EXAMPLE 143′-{([2-(3-Bromophenyl)acetyl][4-hydroxyphenethyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.6 mg

HPLC analysis (condition A): purity 95% (retention time: 3.309 min.)

MS (APCI+): 640 (M+H), 642

EXAMPLE 153′-{([4-Hydroxyphenethyl][2-(4-methoxyphenyl)acetyl]amino)methyl}-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.538 min.)

MS (APCI+): 592 (M+H)

EXAMPLE 16(E)-N-(4-Hydroxyphenethyl)-3-phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-2-propenamidetrifluoroacetate

Yield: 3.8 mg

HPLC analysis (condition A): purity 100% (retention time: 3.465 min.)

MS (APCI+): 670 (M+H)

EXAMPLE 172-(4-Bromophenyl)-N-(4-hydroxyphenethyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 3.5 mg

HPLC analysis (condition A): purity 99% (retention time: 3.538 min.)

MS (APCI+): 736 (M+H), 738

EXAMPLE 182-(Benzyloxy)-N-(4-hydroxyphenethyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 3.8 mg

HPLC analysis (condition A): purity 99% (retention time: 3.416 min.)

MS (APCI+): 688 (M+H)

EXAMPLE 19N-(4-Hydroxyphenethyl)-4-phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}butanamidetrifluoroacetate

Yield: 4.5 mg

HPLC analysis (condition A): purity 100% (retention time: 3.555 min.)

MS (APCI+): 686 (M+H)

EXAMPLE 20N-[2-((4-Hydroxyphenethyl){[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)-2-oxyethyl]benzamidetrifluoroacetate

Yield: 3.0 mg

HPLC analysis (condition A): purity 98% (retention time: 3.281 min.)

MS (APCI+): 701 (M+H)

EXAMPLE 21N-(4-Hydroxyphenethyl)-3-(1H-indol-3-yl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}propanamidetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition A): purity 96% (retention time: 3.455 min.)

MS (APCI+): 711 (M+H)

EXAMPLE 22N-(4-Hydroxyphenethyl)-2-(1H-indol-3-yl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 0.9 mg

HPLC analysis (condition A): purity 90% (retention time: 3.371 min.)

MS (APCI+): 697 (M+H)

EXAMPLE 23N-(4-Hydroxyphenethyl)-4-methyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}pentanamidetrifluoroacetate

Yield: 4.6 mg

HPLC analysis (condition A): purity 100% (retention time: 3.483 min.)

MS (APCI+): 638 (M+H)

EXAMPLE 24(E)-3-(2-Furyl)-N-(4-hydroxyphenethyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-2-propenamidetrifluoroacetate

Yield: 1.8 mg

HPLC analysis (condition A): purity 95% (retention time: 3.391 min.)

MS (APCI+): 660 (M+H)

EXAMPLE 25(E)-N-(4-Hydroxyphenethyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-3-(3-pyridyl)-2-propenamidetrifluoroacetate

Yield: 4.2 mg

HPLC analysis (condition A): purity 95% (retention time: 2.907 min.)

MS (APCI+): 671 (M+H)

EXAMPLE 262-(3-Bromophenyl)-N-(4-hydroxyphenethyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 2.1 mg

HPLC analysis (condition A): purity 94% (retention time: 3.538 min.)

MS (APCI+): 736 (M+H), 738

EXAMPLE 272-(2-Bromophenyl)-N-(4-hydroxyphenethyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 3.2 mg

HPLC analysis (condition A): purity 93% (retention time: 3.518 min.)

MS (APCI+): 736 (M+H), 738

EXAMPLE 28N-(4-Hydroxyphenethyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-2-(4-pyridynylsulfanyl)acetamidetrifluoroacetate

Yield: 6.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.427 min.)

MS (APCI+): 691 (M+H)

EXAMPLE 29N-(4-Hydroxyphenethyl)-2-(4-methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 2.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.666 min.)

MS (APCI+): 688 (M+H)

EXAMPLE 30(E)-N-(4-Hydroxyphenethyl)-3-(4-methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-2-propenamidetrifluoroacetate

Yield: 4.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.709 min.)

MS (APCI+): 700 (M+H)

EXAMPLE 31N-(5-Aminopentyl)-3′-{[[2-(4-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 8.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.633 min.)

MS (APCI+): 628 (M+H), 630

EXAMPLE 32N-(5-Aminopentyl)-3′-{[(4-hydroxyphenethyl)(4-phenylbutanoyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.629 min.)

MS (APCI+): 578 (M+H)

EXAMPLE 33N-(5-Aminopentyl)-3′-{[(4-hydroxyphenethyl)[3-(1H-indol-3-yl)propanoyl]amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.568 min.)

MS (APCI+): 603 (M+H)

EXAMPLE 34N-(5-Aminopentyl)-3′-{[[2-(2-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 8.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.607 min.)

MS (APCI+): 628 (M+H), 630

EXAMPLE 35N-(5-Aminopentyl)-3′-{[[(E)-3-(4-bromophenyl)-2-propenoyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 10.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.689 min.)

MS (APCI+): 640 (M+H), 642

EXAMPLE 36N-(6-Aminohexyl)-3′-{[(4-hydroxyphenethyl)(4-phenylbutanoyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 7.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.660 min.)

MS (APCI+): 592 (M+H)

EXAMPLE 37N-(6-Aminohexyl)-3′-{[(4-hydroxyphenethyl)[3-(1H-indol-3-yl)propanoyl]amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.594 min.)

MS (APCI+): 617 (M+H)

EXAMPLE 38N-(6-Aminohexyl)-3′-{[[(E)-3-(2-furyl)-2-propenoyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.562 min.)

MS (APCI+): 566 (M+H)

EXAMPLE 39N-(6-Aminohexyl)-3′-{[[2-(3-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 8.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.640 min.)

MS (APCI+): 644 (M+H), 646

EXAMPLE 40N-{[3-(Aminomethyl)cyclohexyl]methyl}-3′-{[[2-(4-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.678 min.)

MS (APCI+): 668 (M+H), 670

EXAMPLE 41N-{[3-(Aminomethyl)cyclohexyl]methyl}-3′-{[[2-(benzyloxy)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.604 min.)

MS (APCI+): 620 (M+H)

EXAMPLE 42N-{[3-(Aminomethyl)cyclohexyl]methyl}-3′-{[(4-hydroxyphenethyl)(4-phenylbutanoyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.685 min.)

MS (APCI+): 618 (M+H)

EXAMPLE 43N-{[3-(Aminomethyl)cyclohexyl]methyl}-3′-{[(4-hydroxyphenethyl)[3-(1H-indol-3-yl)propanoyl]amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 0.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.623 min.)

MS (APCI+): 643 (M+H)

EXAMPLE 44N-{[3-(Aminomethyl)cyclohexyl]methyl}-3′-{[(4-hydroxyphenethyl)[2-(1H-indol-3-yl)acetyl]amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.587 min.)

MS (APCI+): 629 (M+H)

EXAMPLE 45N-{[3-(Aminomethyl)cyclohexyl]methyl}-3′-{[[(E)-3-(2-furyl)-2-propenoyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.591 min.)

MS (APCI+): 592 (M+H)

EXAMPLE 46N-{[3-(Aminomethyl)cyclohexyl]methyl)-3′-{[[2-(3-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.673 min.)

MS (APCI+): 668 (M+H), 670

EXAMPLE 47N-{[3-(Aminomethyl)cyclohexyl]methyl}-3′-{[[(E)-3-(4-bromophenyl)-2-propenoyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 8.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.746 min.)

MS (APCI+): 680 (M+H), 682

EXAMPLE 48N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[(4-hydroxyphenethyl)[(E)-3-phenyl-2-propenoyl]amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.630 min.)

MS (APCI+): 602 (M+H)

EXAMPLE 49N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[[2-(4-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.668 min.)

MS (APCI+): 668 (M+H), 670

EXAMPLE 50N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[[2-(benzyloxy)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.593 min.)

MS (APCI+): 620 (M+H)

EXAMPLE 51N-{4-(Aminomethyl)cyclohexyl]methyl}-3′-{[(4-hydroxyphenethyl)(4-phenylbutanoyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.680 min.)

MS (APCI+): 618 (M+H)

EXAMPLE 52N-{4-(Aminomethyl)cyclohexyl]methyl}-3′-{[[2-(benzoylamino)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.521 min.)

MS (APCI+): 633 (M+H)

EXAMPLE 53N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[(4-hydroxyphenethyl)[3-(1H-indol-3-yl)propanoyl]amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.608 min.)

MS (APCI+): 643 (M+H)

EXAMPLE 54N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[(4-hydroxyphenethyl)[2-(1H-indol-3-yl)acetyl]amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.570 min.)

MS (APCI+): 629 (M+H)

EXAMPLE 55N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[[(E)-3-(2-furyl)-2-propenoyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.577 min.)

MS (APCI+): 592 (M+H)

EXAMPLE 56N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[(4-hydroxyphenethyl)[(E)-3-(3-pyridyl)-2-propenoyl]amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.305 min.)

MS (APCI+): 603 (M+H)

EXAMPLE 57N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[[2-(3-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.667 min.)

MS (APCI+): 668 (M+H), 670

EXAMPLE 58N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[[2-(2-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.648 min.)

MS (APCI+): 668 (M+H), 670

EXAMPLE 59N-{[4-(Aminomethyl)cyclohexyl]methyl}-3′-{[(4-hydroxyphenethyl)[2-(4-methoxyphenyl)acetyl]amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.570 min.)

MS (APCI+): 620 (M+H)

EXAMPLE 60N-(4-Aminocyclohexyl)-3′-{[[2-(4-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.617 min.)

MS (APCI+): 640 (M+H), 642

EXAMPLE 61N-(3-Aminopropyl)-3′-{[[2-(4-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 9.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.590 min.)

MS (APCI+): 600 (M+H), 602

EXAMPLE 62N-(3-Aminopropyl)-3′-{[[2-(benzyloxy)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 7.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.527 min.)

MS (APCI+): 552 (M+H)

EXAMPLE 63N-(3-Aminopropyl)-3′-{[(4-hydroxyphenethyl)(4-phenylbutanoyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 8.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.610 min.)

MS (APCI+): 550 (M+H)

EXAMPLE 64 N-(3-Aminopropyl)-3′-{[(4-hydroxyphenethyl)[3-(1H-indol-3-yl)propanoyl]amino]methyl}[1,1′-biphenyl]-3-carboxamide trifluoroacetate

Yield: 7.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.541 min.)

MS (APCI+): 575 (M+H)

EXAMPLE 65N-(3-Aminopropyl)-3′-{[(4-hydroxyphenethyl)[2-(1H-indol-3-yl)acetyl]amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.503 min.)

MS (APCI+): 561 (M+H)

EXAMPLE 66N-(3-Aminopropyl)-3′-{[(4-hydroxyphenethyl)(4-methylpentanoyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 9.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.555 min.)

MS (APCI+): 502 (M+H)

EXAMPLE 67N-(3-Aminopropyl)-3′-{[[2-(3-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 10.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.592 min.)

MS (APCI+): 600 (M+H), 602

EXAMPLE 68N-(3-Aminopropyl)-3′-{[[2-(2-bromophenyl)acetyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 9.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.569 min.)

MS (APCI+): 600 (M+H), 602

EXAMPLE 69N-(3-Aminopropyl)-3′-{[(4-hydroxyphenethyl)[2-(4-methoxyphenyl)acetyl]amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 9.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.498 min.)

MS (APCI+): 552 (M+H)

EXAMPLE 70N-(3-Aminopropyl)-3′-{[[(E)-3-(4-bromophenyl)-2-propenoyl](4-hydroxyphenethyl)amino]methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 10.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.658 min.)

MS (APCI+): 612 (M+H), 614

EXAMPLE 71N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl][(E)-3-phenyl-2-propenoyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate 1) 2-[(3-Bromobenzoyl)amino]ethylcarbamic acid Wangresin ester

A mixture of 4-nitrophenoxycarbonyl Wang resin (7.00 g),N-(2-aminoethyl)-3-bromobenzamide (3.52 g), DIEA (4.26 ml) and DMF (60ml) was stirred at room temperature for 20 hours. The solvent wasremoved by filtration, and the resultant resin was washed with DMF, THFand methanol in this order and then dried at 50° C. under reducedpressure to give the title compound (6.8 g). The amount of the compoundcarried on the resin was 0.94 mmol/g (elemental analysis: calculatedfrom 7.51% Br). The resultant resin (5 beads) was treated withtrifluoroacetic acid-dichloromethane (1:1; 50 ml) to giveN-(2-aminoethyl)-3-bromobenzamide which was then analyzed in HPLC andmeasured by mass spectrometry.

HPLC analysis (condition A): purity 96% (retention time: 1.208 min.)

MS (APCI+): 243 (M+H), 245

2) 2-{[(3′-Formyl[1,1′-biphenyl]-3-yl)carbonyl]amino}ethylcarbamic acidWang resin ester

Palladium tetrakistriphenyl phosphine (706 mg) and 2 M aqueous sodiumcarbonate (30.6 ml) were added to a suspension of2-[(3-bromobenzoyl)amino]ethylcarbamic acid Wang resin ester (6.50 g) in1,2-dimethoxyethane (200 ml), and 3-formylphenylboric acid (4.58 g) wasfurther added thereto, and the mixture was stirred at 80° C. for 20hours. The solvent was removed by filtration, and the resultant resinwas washed with DMF, THF and methanol in this order and then dried at50° C. under reduced pressure to give the title compound (6.68 g). Theresultant resin (5 beads) was treated with trifluoroaceticacid-dichloromethane (1:1; 50 ml) to giveN-(2-aminoethyl)-3′-formyl[1,1′-biphenyl]-3-carboxamide which was thenanalyzed in HPLC and measured by mass spectrometry.

HPLC analysis (condition A): purity 95% (retention time: 2.295 min.)

MS (APCI+): 269 (M+H)

3)2-{[(3′-{[(4-(Aminosulfonyl)phenethyl)amino]methyl}[1,1′-biphenyl]-3-yl)carbonyl]amino}ethylcarbamicacid Wang resin ester

A mixture of2-{[(3′-formyl[1,1′-biphenyl]-3-yl)carbonyl]amino}ethylcarbamic acidWang resin ester (30 mg), 4-(2-aminosulfonyl)benzenesulfonamide (28 mg)and a solution of 5% acetic acid in dichloromethane (2 ml) was stirredat room temperature for 30 minutes, and sodium triacetoxy borohydride(30 mg) was further added thereto, and the mixture was stirred at roomtemperature for 15 hours. The solvent was removed by filtration, and theresultant resin was washed with DMF, a mixed solvent of DMF-water (1:1),DMF, THF and methanol in this order and then dried at 50° C. underreduced pressure to give the title compound (30 mg). The resultant resin(5 beads) was treated with trifluoroacetic acid-dichloromethane (1:1; 50ml) to giveN-(2-aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidewhich was then analyzed in HPLC and measured by mass spectrometry.

HPLC analysis (condition A): purity 88% (retention time: 0.857 min.)

MS (APCI−): 451 (M−H)

4)N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl][(E)-3-phenyl-2-propenoyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Cinnamic acid (29 mg), DIPCI (27 ml) and HOAT (23 mg) were added to asuspension of2-{[(3′-{[(4-(aminosulfonyl)phenethyl)amino]methyl}[1,1′-biphenyl]-3-yl)carbonyl]amino}ethylcarbamicacid Wang resin ester (30 mg) in DMF (2 ml), and the mixture was stirredat room temperature for 15 hours. The solvent was removed by filtration,and the resultant resin was washed with DMF, THF and methanol in thisorder and then dried at 50° C. under reduced pressure. The resultantresin was treated with trifluoroacetic acid-dichloromethane (1:1; 1 ml)and then purified by preparative HPLC to give the title compound (5.4mg).

¹H-NMR (Acetone-d₆) •: 3.00–3.20 (2H, m), 3.70–3.90 (4H, m), 4.00–4.15(2H, m), 4.85 (2H,s), 6.45–6.60 (1H, m), 7.05–7.20 (1H, m), 7.25–8.00(17H, m), 8.31 (1H, s).

HPLC analysis (condition B): purity 97% (retention time: 1.492 min.)

MS (APCI−): 581 (M−H)

The following compounds were produced in the same manner as in Example71.

EXAMPLE 72N-(2-Aminoethyl)-3′-{[(4-(aminosulfonyl)phenethyl][2-(4-bromophenyl)acetyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.535 min.)

MS (APCI−): 647 (M−H), 649

EXAMPLE 73N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl][2-(benzyloxy)acetyl]amino}methyl}[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 8.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.445 min.)

MS (APCI−): 599 (M−H)

EXAMPLE 74N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl](4-phenylbutanoyl)amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 8.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.540 min.)

MS (APCI−): 597 (M−H)

EXAMPLE 75N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl][(E)-3-(2-furyl)-2-propenoyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.427 min.)

MS (APCI−): 571 (M−H)

EXAMPLE 76N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl][2-(3-bromophenyl)acetyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.524 min.)

MS (APCI−): 647 (M−H), 649

EXAMPLE 77N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl][2-(2-bromophenyl)acetyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 9.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.499 min.)

MS (APCI−): 647 (M−H), 649

EXAMPLE 78N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl][(E)-3-(4-methoxyphenyl)-2-propenoyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.498 min.)

MS (APCI−): 611 (M−H)

EXAMPLE 79N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl][2-(4-methoxyphenyl)acetyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.431 min.)

MS (APCI−): 599 (M−H)

EXAMPLE 80N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl][2-(4-hydroxyphenyl)acetyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.325 min.)

MS (APCI−): 585 (M−H)

EXAMPLE 81N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl][(E)-3-(4-hydroxyphenyl)-2-propenoyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.347 min.)

MS (APCI−): 597 (M−H)

EXAMPLE 82N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)phenethyl][3-(4-hydroxyphenyl)propanoyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.592 min.)

MS (APCI−): 599 (M−H)

EXAMPLE 83N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)benzyl][(E)-3-phenyl-2-propenoyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.476 min.)

MS (APCI−): 567 (M−H)

EXAMPLE 84N-(2-Aminoethyl)-3′-({[4-(aminosulfonyl)benzyl][(E)-3-(4-methoxyphenyl)-2-propenoyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.478 min.)

MS (APCI−): 597 (M−H)

EXAMPLE 85N-(2-Aminoethyl)-3′-({[3-(1H-indol-3-yl)propanoyl][2-(4-pyridinyl)ethyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.335 min.)

MS (APCI−): 544 (M−H)

EXAMPLE 86N-(2-Aminoethyl)-3′-({[2-(1H-indol-3-yl)acetyl][2-(2-oxo-1-pyrrolidinyl)ethyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.425 min.)

MS (APCI−): 550 (M−H)

EXAMPLE 87N-(2-Aminoethyl)-3′-({[4-phenylbutanoyl][2-(2-thienyl)ethyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 2.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.722 min.)

MS (APCI−): 524 (M−H)

EXAMPLE 88N-(2-Aminoethyl)-3′-({[2-(3-bromophenyl)acetyl][2-(2-thienyl)ethyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 2.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.722 min.)

MS (APCI+): 576 (M+H), 578

EXAMPLE 89N-(2-Aminoethyl)-3′-({[(E)-3-(4-hydroxyphenyl)-2-propenoyl][2-(2-thienyl)ethyl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 2.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.549 min.)

MS (APCI−): 524 (M−H)

EXAMPLE 90N-(2-Aminoethyl)-3′-({[(E)-3-phenyl-2-propenoyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.652 min.)

MS (APCI+): 574 (M+H)

EXAMPLE 91N-(2-Aminoethyl)-3′-({[(E)-3-(4-methoxyphenyl)-2-propenoyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.647 min.)

MS (APCI+): 604 (M+H)

EXAMPLE 92N-(2-Aminoethyl)-3′-({[(E)-3-phenyl-2-propenoyl](3-phenylpropyl)amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.743 min.)

MS (APCI−): 516 (M−H)

EXAMPLE 93N-(2-Aminoethyl)-3′-({[(E)-3-(4-methoxyphenyl)-2-propenoyl](3-phenylpropyl)amino}methyl)[1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 7.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.740 min.)

MS (APCI−): 546 (M−H)

EXAMPLE 943′-({[4-(Aminosulfonyl)phenethyl][(E)-3-(4-methoxyphenyl)-2-propenoyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate 1) 3-Bromo-N-formylresin-N-[2-(1-pyrrolidinyl)ethyl]benzamide

A mixture of 4-(4-formyl-3-methoxyphenoxy)butyrylaminomethyl resin(formyl resin: 4.20 g), 1-(2-aminoethyl)pyrrolidine (2.13 ml) and asolution of 5% acetic acid in dichloromethane (100 ml) was stirred atroom temperature for 30 minutes, and then sodium triacetoxy borohydride(3.56 g) was added thereto, and the mixture was further stirred at roomtemperature for 15 hours. The solvent was removed by filtration, and theresin was washed with DMF, a mixed solvent of DMF-water (1:1), DMF, THFand methanol in this order and then dried at 50° C. under reducedpressure. The resultant resin was suspended in DMF (80 ml), and3-bromobenzoic acid (3.38 g), PyBOP (8.74 g) and DIEA (2.93 ml) wereadded thereto, and the mixture was stirred at room temperature for 15hours. The solvent was removed by filtration, and the resultant resinwas washed with DMF, THF and methanol in this order and dried at 50° C.under reduced pressure to give the title compound (6.18 g). The amountof the compound carried on the resin was 0.95 mmol/g (elementalanalysis: calculated from 7.55% Br). The resultant resin (5 beads) wastreated with trifluoroacetic acid-dichloromethane (1:1; 50 ml) to give3-bromo-N-[2-(1-pyrrolidinyl)ethyl]benzamide which was then analyzed inHPLC and measured by mass spectrometry.

HPLC analysis (condition B): purity 98% (retention time: 1.460 min.)

MS (APCI+): 297 (M+H), 299

2) 3′-Formyl-N-formylresin-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamide

The title compound was produced in the same manner as in 2) in Example71.

HPLC analysis (condition B): purity 95% (retention time: 1.214 min.)

MS (APCI+): 323 (M+H)

3) 3′-({[4-(Aminosulfonyl)phenethyl]amino}methyl)-N-formylresin-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamide

The title compound was produced in the same manner as in 3) in Example71.

Yield: 30 mg

HPLC analysis (condition B): purity 73% (retention time: 1.030 min.)

MS (APCI+): 507 (M+H)

4)3′-({[4-(Aminosulfonyl)phenethyl][(E)-3-(4-methoxyphenyl)-2-propenoyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

The title compound was produced in the same manner as in 4) in Example71.

Yield: 4.7 mg

¹H-NMR (Acetone-d₆) •: 1.90–2.20 (4H, m), 3.05 (2H, m), 3.22 (2H, m),3.40–3.65 (7H, m), 3.70–4.00 (4H, m), 4.80 (2H,s), 6.40–6.60 (1H, m),6.90–7.05 (2H, m), 7.20–8.00 (15H, m), 8.22 (1H, s).

HPLC analysis (condition B): purity 100% (retention time: 1.543 min.)

MS (APCI−): 667 (M1H)

The following compounds were produced in the same manner as in Example94.

EXAMPLE 953′-({[4-(Aminosulfonyl)phenethyl][2-(4-bromophenyl)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.7 mg

HPLC analysis (condition B): purity 91% (retention time: 1.577 min.)

MS (APCI+): 703 (M+H), 705

EXAMPLE 963′-({[4-(Aminosulfonyl)phenethyl][2-(3-bromophenyl)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.571 min.)

MS (APCI+): 703 (M+H), 705

EXAMPLE 973′-({[4-(Aminosulfonyl)phenethyl][2-(2-bromophenyl)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.543 min.)

MS (APCI+): 703 (M+H), 705

EXAMPLE 983′-({[4-(Aminosulfonyl)phenethyl][(E)-3-phenyl-2-propenoyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.543 min.)

MS (APCI+): 637 (M+H)

EXAMPLE 993′-({[4-(Aminosulfonyl)phenethyl][2-(benzyloxy)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.497 min.)

MS (APCI+): 655 (M+H)

EXAMPLE 1003′-({[4-(Aminosulfonyl)phenethyl](4-phenylbutanoyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.581 min.)

MS (APCI+): 653 (M+H)

EXAMPLE 1013′-({[4-(Aminosulfonyl)phenethyl][3-(1H-indol-3-yl)propanoyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.524 min.)

MS (APCI+): 678 (M+H)

EXAMPLE 1023′-({[4-(Aminosulfonyl)phenethyl][2-(4-methoxyphenyl)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.3 mg HPLC analysis (condition B): purity 100% (retention time:1.467 min.)

MS (APCI+): 655 (M+H)

EXAMPLE 1033′-({[4-(Aminosulfonyl)phenethyl][2-(3-methoxyphenyl)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.491 min.)

MS (APCI+): 655 (M+H)

EXAMPLE 1043′-({[4-(Aminosulfonyl)phenethyl][2-(3-fluorophenyl)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.490 min.)

MS (APCI+): 643 (M+H)

EXAMPLE 1053′-({[4-(Aminosulfonyl)phenethyl][2-(benzoylamino)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.413 min.)

MS (APCI+): 668 (M+H)

EXAMPLE 1063′-({[4-(Aminosulfonyl)benzyl][2-(4-bromophenyl)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.564 min.)

MS (APCI+): 689 (M+H), 691

EXAMPLE 1073′-({[4-(Aminosulfonyl)benzyl][2-(2-bromophenyl)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.534 min.)

MS (APCI+): 689 (M+H), 691

EXAMPLE 1083′-({[4-(Aminosulfonyl)benzyl][(E)-3-phenyl-2-propenoyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.532 min.)

MS (APCI+): 623 (M+H)

EXAMPLE 1093′-({[4-(Aminosulfonyl)benzyl][2-(benzyloxy)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.480 min.)

MS (APCI+): 641 (M+H)

EXAMPLE 1103′-({[4-(Aminosulfonyl)benzyl](4-phenylbutanoyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.576 min.)

MS (APCI+): 639 (M+H)

EXAMPLE 1113′-({[4-(Aminosulfonyl)benzyl][3-(1H-indol-3-yl)propanoyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 2.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.503 min.)

MS (APCI+): 664 (M+H)

EXAMPLE 1123′-({[4-(Aminosulfonyl)benzyl][2-(3-methoxyphenyl)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.485 min.)

MS (APCI−): 641 (M−H)

EXAMPLE 1133′-({[4-(Aminosulfonyl)benzyl][(E)-3-(4-methoxyphenyl)-2-propenoyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.527 min.)

MS (APCI+): 653 (M+H)

EXAMPLE 1143′-({[4-(Aminosulfonyl)benzyl][2-(3-fluorophenyl)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.494 min.)

MS (APCI+): 629 (M+H)

EXAMPLE 1153′-({[2-(4-Bromophenyl)acetyl][2-(4-pyridinyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.230 min.)

MS (APCI+): 625 (M+H), 627

EXAMPLE 1163′-({[2-(3-Bromophenyl)acetyl][2-(4-pyridinyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.236 min.)

MS (APCI+): 625 (M+H), 627

EXAMPLE 1173′-({[2-(2-Bromophenyl)acetyl][2-(4-pyridinyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.320 min.)

MS (APCI+): 625 (M+H), 627

EXAMPLE 1183′-({[(E)-3-Phenyl-2-propenoyl][2-(4-pyridinyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.316 min.)

MS (APCI+): 559 (M+H)

EXAMPLE 1193′-({(4-Phenylbutanoyl)[2-(4-pyridinyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.234 min.)

MS (APCI+): 575 (M+H)

EXAMPLE 1203′-({[3-(1H-Indol-3-yl)propanoyl][2-(4-pyridinyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.308 min.)

MS (APCI+): 600 (M+H)

EXAMPLE 1213′-({[2-(4-Methoxyphenyl)acetyl][2-(4-pyridinyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 6.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.264 min.)

MS (APCI+): 577 (M+H)

EXAMPLE 1223′-({[2-(2-Bromophenyl)acetyl][2-(2-thienyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 2.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.749 min.)

MS (APCI+): 630 (M+H), 632

EXAMPLE 1233′-({[2-(2-Thienyl)ethyl][(E)-3-phenyl-2-propenoyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.728 min.)

MS (APCI+): 564 (M+H)

EXAMPLE 1243′-({[2-(Benzyloxy)acetyl][2-(2-thienyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.682 min.)

MS (APCI+): 582 (M+H)

EXAMPLE 1253′-({(4-Phenylbutanoyl)[2-(2-thienyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.776 min.)

MS (APCI+): 580 (M+H)

EXAMPLE 1263′-({[3-(1H-Indol-3-yl)propanoyl][2-(2-thienyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.701 min.)

MS (APCI+): 605 (M+H)

EXAMPLE 1273′-({[2-(4-Methoxyphenyl)acetyl][2-(2-thienyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.667 min.)

MS (APCI+): 582 (M+H)

EXAMPLE 1283′-({[2-(3-Methoxyphenyl)acetyl][2-(2-thienyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.672 min.)

MS (APCI+): 582 (M+H)

EXAMPLE 1293′-({[(E)-3-(4-Methoxyphenyl)-2-propenoyl][2-(2-thienyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.715 min.)

MS (APCI+): 594 (M+H)

EXAMPLE 1303′-({[2-(3-Fluorophenyl)acetyl][2-(2-thienyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.700 min.)

MS (APCI+): 570 (M+H)

EXAMPLE 1313′-({[2-(Benzoylamino)acetyl][2-(2-thienyl)ethyl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.583 min.)

MS (APCI+): 595 (M+H)

EXAMPLE 1323′-({[2-(4-Bromophenyl)acetyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.753 min.)

MS (APCI+): 694 (M+H), 696

EXAMPLE 1333′-({[2-(3-Bromophenyl)acetyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.729 min.)

MS (APCI+): 694 (M+H), 696

EXAMPLE 1343′-({[2-(2-Bromophenyl)acetyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.7 mg

HPLC analysis (condition B): purity 98% (retention time: 1.721 min.)

MS (APCI+): 694 (M+H), 696

EXAMPLE 1353′-({[(E)-3-Phenyl-2-propenoyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.705 min.)

MS (APCI+): 628 (M+H)

EXAMPLE 1363′-({[2-(Benzyloxy)acetyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 2.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.662 min.)

MS (APCI+): 646 (M+H)

EXAMPLE 1373′-({(4-Phenylbutanoyl)[4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.759 min.)

MS (APCI+): 644 (M+H)

EXAMPLE 1383′-({[3-(1H-Indol-3-yl)propanoyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.680 min.)

MS (APCI+): 669 (M+H)

EXAMPLE 1393′-({[2-(4-Methoxyphenyl)acetyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.652 min.)

MS (APCI+): 646 (M+H)

EXAMPLE 1403′-({[2-(3-Methoxyphenyl)acetyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.651 min.)

MS (APCI+): 582 (M+H)

EXAMPLE 1413′-({[(E)-3-(4-Methoxyphenyl)-2-propenoyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.708 min.)

MS (APCI+): 658 (M+H)

EXAMPLE 1423′-({[2-(3-Fluorophenyl)acetyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.673 min.)

MS (APCI+): 634 (M+H)

EXAMPLE 1433′-({[2-(Benzoylamino)acetyl][4-(1,2,3-thiadiazol-4-yl]amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.566 min.)

MS (APCI+): 659 (M+H)

EXAMPLE 1443′-({[2-(4-Bromophenyl)acetyl](3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.831 min.)

MS (APCI+): 638 (M+H), 640

EXAMPLE 1453′-({[2-(3-Bromophenyl)acetyl](3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.822 min.)

MS (APCI+): 638 (M+H), 640

EXAMPLE 1463′-({[2-(2-Bromophenyl)acetyl](3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition B): purity 98% (retention time: 1.814 min.)

MS (APCI+): 638 (M+H), 640

EXAMPLE 1473′-({[(E)-3-Phenyl-2-propenoyl](3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.798 min.)

MS (APCI+): 572 (M+H)

EXAMPLE 1483′-({[2-(Benzyloxy)acetyl](3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.754 min.)

MS (APCI+): 590 (M+H)

EXAMPLE 1493′-({(4-Phenylbutanoyl)(3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.844 min.)

MS (APCI+): 588 (M+H)

EXAMPLE 1503′-({[3-(1H-Indol-3-yl)propanoyl](3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 1.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.761 min.)

MS (APCI+): 613 (M+H)

EXAMPLE 1513′-([{2-(4-Methoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 3.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.724 min.)

MS (APCI+): 590 (M+H)

EXAMPLE 1523′-({[2-(3-Methoxyphenyl)acetyl](3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.737 min.)

MS (APCI+): 590 (M+H)

EXAMPLE 1533′-({[(E)-3-(4-Methoxyphenyl)-2-propenoyl](3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 4.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.791 min.)

MS (APCI+): 602 (M+H)

EXAMPLE 1543′-({[2-(3-Fluorophenyl)acetyl](3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.758 min.)

MS (APCI+): 578

EXAMPLE 1553′-({[2-(Benzoylamino)acetyl](3-phenylpropyl)amino}methyl)-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamidetrifluoroacetate

Yield: 5.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.648 min.)

MS (APCI+): 603 (M+H)

EXAMPLE 156 Methyl4-[([2-(4-bromophenyl)acetyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 1.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.740 min.)

MS (APCI+): 668 (M+H), 670

EXAMPLE 157 Methyl4-[([2-(3-bromophenyl)acetyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 3.1 mg

HPLC analysis (condition B): purity 94% (retention time: 1.735 min.)

MS (APCI+): 668 (M+H), 670

EXAMPLE 158 Methyl4-[([2-(2-Bromophenyl)acetyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 5.7 mg

HPLC analysis (condition B): purity 95% (retention time: 1.718 min.)

MS (APCI+): 668 (M+H), 670

EXAMPLE 159 Methyl4-[([(E)-3-phenyl-2-propenoyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 1.5 mg

HPLC analysis (condition B): purity 97% (retention time: 1.700 min.)

MS (APCI+): 602 (M+H)

EXAMPLE 160 Methyl4-[([2-(Benzyloxy)acetyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 1.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.648 min.)

MS (APCI+): 620 (M+H)

EXAMPLE 161 Methyl4-[({(4-Phenylbutanoyl){[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 5.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.748 min.)

MS (APCI+): 618 (M+H)

EXAMPLE 162 Methyl4-[({[3-(1H-Indol-3-yl)propanoyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 0.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.674 min.)

MS (APCI+): 643 (M+H)

EXAMPLE 163 Methyl4-[({[2-(3-Methoxyphenyl)acetyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.641 min.)

MS (APCI+): 620 (M+H)

EXAMPLE 164 Methyl4-[({[(E)-3-(4-Methoxyphenyl)-2-propenoyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 0.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.697 min.)

MS (APCI+): 632 (M+H)

EXAMPLE 165 Methyl4-[({[2-(3-Fluorophenyl)acetyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 4.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.672 min.)

MS (APCI+): 608 (M+H)

EXAMPLE 166 Methyl6-[(2-(4-Bromophenyl)acetyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 3.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.696 min.)

MS (APCI+): 648 (M+H), 650

EXAMPLE 167 Methyl6-[(2-(3-Bromophenyl)acetyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 1.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.691 min.)

MS (APCI+): 648 (M+H), 650

EXAMPLE 168 Methyl6-[(2-(2-Bromophenyl)acetyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 2.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.670 min.)

MS (APCI+): 648 (M+H), 650

EXAMPLE 169 Methyl6-([(E)-3-Phenyl-2-propenoyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.655 min.)

MS (APCI+): 582 (M+H)

EXAMPLE 170 Methyl6-([4-Phenylbutanoyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 3.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.699 min.)

MS (APCI+): 598 (M+H)

EXAMPLE 171 Methyl6-([3-(1H-Indol-3-yl)propanoyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.629 min.)

MS (APCI+): 623 (M+H)

EXAMPLE 172 Methyl6-([(E)-3-(4-Methoxyphenyl)-2-propenoyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 3.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.659 min.) MS(APCI+): 612 (M+H)

EXAMPLE 173 Methyl6-([2-(3-Fluorophenyl)acetyl]{[3′-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 2.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.620 min.)

MS (APCI+): 588 (M+H)

EXAMPLE 174N-[4-(Aminosulfonyl)phenethyl]-2-(4-bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate 1)4-{3-[1-(3-Bromobenzoyl)-4-piperidinyl]propyl}-1-piperidine carboxylicacid Wang resin ester

A mixture of 4-nitrophenoxycarbonyl Wang resin (6.00 g),(3-bromophenyl){4-[3-(4-piperidinyl)propyl]-1-piperidinyl}methanonehydrochloride (4.66 g), DIEA (3.76 ml) and DMF (50 ml) was stirred atroom temperature for 20 hours. The solvent was removed by filtration,and the resultant resin was washed with DMF, THF and methanol in thisorder and then dried at 50° C. under reduced pressure to give the titlecompound (6.95 g). The amount of the compound carried on the resin was0.72 mmol/g (elemental analysis: calculated from 5.77% Br). Theresultant resin (5 beads) was treated with trifluoroaceticacid-dichloromethane (1:1; 50 ml) to give(3-bromophenyl){4-[3-(4-piperidinyl)propyl}-1-piperidinyl}methanonewhich was then analyzed in HPLC and measured by mass spectrometry.

HPLC analysis (condition B): purity 97% (retention time: 1.437 min.)

MS (APCI+): 393 (M+H), 395

2)4-{3-{1-[(3′-Formyl[1,1′-biphenyl]-3-yl)carbonyl]-4-piperidinyl]propyl}-1-piperidinecarboxylic acid Wang resin ester

The title compound was obtained in the same manner as in 2) in Example71.

Yield: 7.60 g

HPLC analysis (condition B): purity 94% (retention time: 1.484 min.)

MS (APCI+): 419 (M+H)

3)4-{3-{1-[(3′-({[4-(Aminosulfonyl)phenethyl]amino}methyl)[1,1′-biphenyl]-3-yl)carbonyl]-4-piperidinyl]propyl}-1-piperidinecarboxylic acid Wang resin ester

The title compound was obtained in the same manner as in 3) in Example71.

Yield: 30 mg

HPLC analysis (condition B): purity 67% (retention time: 1.293 min.)

MS (APCI+): 603 (M+H)

4)N-[4-(Aminosulfonyl)phenethyl]-2-(4-bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

The title compound was obtained in the same manner as in 4) in Example71.

Yield: 6.0 mg

¹H-NMR (Acetone-d₆) •: 1.00–2.00 (16H, m), 2.90–3.40 (8H, m), 3.40–3.60(2H, m), 3.60–3.80 (2H, m), 3.81 (2H,s), 4.78 (2H, s), 6.55–6.65 (2H,m), 7.14–7.25 (4H, m), 7.30–7.50 (8H, m), 7.60–7.90 (2H, m).

HPLC analysis (condition B): purity 98% (retention time: 1.702 min.)

MS (APCI+): 798 (M+H), 800

The following compounds were produced in the same manner as in Example174.

EXAMPLE 175N-[4-(Aminosulfonyl)phenethyl]-2-(3-bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 6.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.687 min.)

MS (APCI−): 797 (M−H), 799

EXAMPLE 176N-[4-(Aminosulfonyl)phenethyl]-2-(2-bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 6.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.677 min.)

MS (APCI−): 797 (M−H), 799

EXAMPLE 177(E)-N-[4-(Aminosulfonyl)phenethyl]-3-phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-2-propenamidetrifluoroacetate

Yield: 6.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.656 min.)

MS (APCI−): 731 (M−H)

EXAMPLE 178N-[4-(Aminosulfonyl)phenethyl]-2-(benzyloxy)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 6.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.625 min.)

MS (APCI−): 751 (M−H)

EXAMPLE 179N-[4-(Aminosulfonyl)phenethyl]-4-phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}butanamidetrifluoroacetate

Yield: 5.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.700 min.)

MS (APCI−): 747 (M−H)

EXAMPLE 180N-[4-(Aminosulfonyl)phenethyl]-2-(4-methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl)acetamidetrifluoroacetate

Yield: 1.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.615 min.)

MS (APCI−): 749 (M−H)

EXAMPLE 181N-[4-(Aminosulfonyl)phenethyl]-2-(3-methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.619 min.)

MS (APCI−): 749 (M−H)

EXAMPLE 182(E)-N-[4-(Aminosulfonyl)phenethyl]-3-(4-methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-2-propenamidetrifluoroacetate

Yield: 1.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.661 min.)

MS (APCI−): 761 (M−H)

EXAMPLE 183N-[4-(Aminosulfonyl)phenethyl]-2-(3-fluorophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 4.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.633 min.)

MS (APCI−): 737 (M−H)

EXAMPLE 184N-[2-([4-(Aminosulfonyl)phenethyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)-2-oxyethyl]benzamidetrifluoroacetate

Yield: 1.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.563 min.)

MS (APCI−): 762 (M−H)

EXAMPLE 185N-[4-(Aminosulfonyl)benzyl]-2-(4-bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 1.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.698 min.)

MS (APCI−): 783 (M−H), 785

EXAMPLE 186N-[4-(Aminosulfonyl)benzyl]-2-(3-bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 6.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.686 min.)

MS (APCI−): 783 (M−H), 785

EXAMPLE 187N-[4-(Aminosulfonyl)benzyl]-2-(2-bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 2.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.676 min.)

MS (APCI−): 783 (M−H), 785

EXAMPLE 188(E)-N-[4-(Aminosulfonyl)benzyl]-3-phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl)carbonyl)[1,1′-biphenyl]-3-yl]methyl}-2-propenamidetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.615 min.)

MS (APCI−): 717 (M−H)

EXAMPLE 189N-[4-(Aminosulfonyl)benzyl]-2-(benzyloxy)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 2.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.622 min.)

MS (APCI−): 735 (M−H)

EXAMPLE 190N-[4-(Aminosulfonyl)benzyl]-4-phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}butanamidetrifluoroacetate

Yield: 5.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.692 min.)

MS (APCI−): 733 (M−H)

EXAMPLE 191N-[4-(Aminosulfonyl)benzyl]-2-(4-methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 3.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.603 min.)

MS (APCI−): 735 (M−H)

EXAMPLE 192N-[4-(Aminosulfonyl)benzyl]-2-(3-methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 0.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.609 min.)

MS (APCI−): 735 (M−H)

EXAMPLE 193(E)-N-[4-(Aminosulfonyl)benzyl]-3-(4-methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl)carbonyl)[1,1′-biphenyl]-3-yl]methyl}-2-propenamidetrifluoroacetate

Yield: 3.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.647 min.)

MS (APCI−): 747 (M−H)

EXAMPLE 194N-[4-(Aminosulfonyl)benzyl]-2-(3-fluorophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 5.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.624 min.)

MS (APCI−): 723 (M−H)

EXAMPLE 195N-[2-([4-(Aminosulfonyl)benzyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)-2-oxyethyl]benzamidetrifluoroacetate

Yield: 1.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.540 min.)

MS (APCI−): 748 (M−H)

EXAMPLE 1962-(4-Bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(4-pyridinyl)ethyl]acetamidetrifluoroacetate

Yield: 7.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.469 min.)

MS (APCI+): 721 (M+H), 723

EXAMPLE 1972-(3-Bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(4-pyridinyl)ethyl]acetamidetrifluoroacetate

Yield: 6.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.491 min.)

MS (APCI+): 721 (M+H), 723

EXAMPLE 1982-(2-Bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(4-pyridinyl)ethyl]acetamidetrifluoroacetate

Yield: 6.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.470 min.)

MS (APCI+): 721 (M+H), 723

EXAMPLE 199(E)-3-Phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(4-pyridinyl)ethyl]-2-propenamidetrifluoroacetate

Yield: 6.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.454 min.)

MS (APCI+): 655 (M+H)

EXAMPLE 2004-Phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(4-pyridinyl)ethyl]butanamidetrifluoroacetate

Yield: 2.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.495 min.)

MS (APCI+): 672 (M+H)

EXAMPLE 2013-(1H-Indol-3-yl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(4-pyridinyl)ethyl]propanamidetrifluoroacetate

Yield: 2.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.416 min.)

MS (APCI+): 694 (M+H)

EXAMPLE 2022-(4-Methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(4-pyridinyl)ethyl]acetamidetrifluoroacetate

Yield: 5.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.417 min.)

MS (APCI+): 673 (M+H)

EXAMPLE 2032-(3-Methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(4-pyridinyl)ethyl]acetamidetrifluoroacetate

Yield: 4.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.419 min.)

MS (APCI+): 673 (M+H)

EXAMPLE 204(E)-3-(4-Methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(4-pyridinyl)ethyl]-2-propenamidetrifluoroacetate

Yield: 5.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.447 min.)

MS (APCI+): 685 (M+H)

EXAMPLE 2052-(3-Fluorophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(4-pyridinyl)ethyl]acetamidetrifluoroacetate

Yield: 6.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.430 min.)

MS (APCI+): 661 (M+H)

EXAMPLE 206N-(2-Oxo-2-{{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}[2-(4-pyridinyl)ethyl]amino}ethyl)benzamidetrifluoroacetate

Yield: 6.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.369 min.)

MS (APCI+): 686 (M+H)

EXAMPLE 2072-(4-Bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(2-thienyl)ethyl]acetamidetrifluoroacetate

Yield: 2.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.871 min.)

MS (APCI+): 726 (M+H), 728

EXAMPLE 2082-(3-Bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(2-thienyl)ethyl]acetamidetrifluoroacetate

Yield: 1.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.860 min.)

MS (APCI+): 726 (M+H), 728

EXAMPLE 2092-(2-Bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(2-thienyl)ethyl]acetamidetrifluoroacetate

Yield: 1.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.859 min.)

MS (APCI+): 726 (M+H), 728

EXAMPLE 210(E)-3-Phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(2-thienyl)ethyl]-2-propenamidetrifluoroacetate

Yield: 2.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.835 min.)

MS (APCI+): 660 (M+H)

EXAMPLE 2112-(Benzyloxy)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(2-thienyl)ethyl]acetamidetrifluoroacetate

Yield: 2.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.803 min.)

MS (APCI+): 678 (M+H)

EXAMPLE 2124-Phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(2-thienyl)ethyl]butanamidetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.879 min.)

MS (APCI+): 676 (M+H)

EXAMPLE 2133-(1H-Indol-3-yl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(2-thienyl)ethyl]propanamidetrifluoroacetate

Yield: 1.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.804 min.)

MS (APCI+): 701 (M+H)

EXAMPLE 2142-(4-Methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(2-thienyl)ethyl]acetamidetrifluoroacetate

Yield: 1.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.753 min.)

MS (APCI+): 678 (M+H)

EXAMPLE 2152-(3-Methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(2-thienyl)ethyl]acetamidetrifluoroacetate

Yield: 2.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.781 min.)

MS (APCI+): 678 (M+H)

EXAMPLE 216(E)-3-(4-Methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(2-thienyl)ethyl]-2-propenamidetrifluoroacetate

Yield: 2.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.830 min.)

MS (APCI+): 690 (M+H)

EXAMPLE 2172-(3-Fluorophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[2-(2-thienyl)ethyl]acetamidetrifluoroacetate

Yield: 2.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.807 min.)

MS (APCI+): 666 (M+H)

EXAMPLE 218N-(2-Oxo-2-{{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}[2-(2-thienyl)ethyl]amino}ethyl)benzamidetrifluoroacetate

Yield: 0.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.698 min.)

MS (APCI+): 691 (M+H)

EXAMPLE 2192-(4-Bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[3-(1,2,3-thiadiazol-4-yl)benzyl]acetamidetrifluoroacetate

Yield: 5.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.862 min.)

MS (APCI+): 790 (M+H), 792

EXAMPLE 2202-(3-Bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[3-(1,2,3-thiadiazol-4-yl)benzyl]acetamidetrifluoroacetate

Yield: 5.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.852 min.)

MS (APCI+): 790 (M+H), 792

EXAMPLE 2212-(2-Bromophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[3-(1,2,3-thiadiazol-4-yl)benzyl]acetamidetrifluoroacetate

Yield: 4.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.841 min.)

MS (APCI+): 790 (M+H), 792

EXAMPLE 222(E)-3-Phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[3-(1,2,3-thiadiazol-4-yl)benzyl]-2-propenamidetrifluoroacetate

Yield: 3.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.809 min.)

MS (APCI+): 724 (M+H)

EXAMPLE 2232-(Benzyloxy)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[3-(1,2,3-thiadiazol-4-yl)benzyl]acetamidetrifluoroacetate

Yield: 0.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.781 min.)

MS (APCI+): 742 (M+H)

EXAMPLE 2244-Phenyl-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[3-(1,2,3-thiadiazol-4-yl)benzyl]butanamidetrifluoroacetate

Yield: 4.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.863 min.)

MS (APCI+): 740 (M+H)

EXAMPLE 2253-(1H-Indol-3-yl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[3-(1,2,3-thiadiazol-4-yl)benzyl]propanamidetrifluoroacetate

Yield: 2.4 mg

HPLC analysis (condition B): purity 92% (retention time: 1.793 min.)

MS (APCI+): 765 (M+H)

EXAMPLE 2262-(4-Methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[3-(1,2,3-thiadiazol-4-yl)benzyl]acetamidetrifluoroacetate

Yield: 2.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.775 min.)

MS (APCI+): 742 (M+H)

EXAMPLE 2272-(3-Methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[3-(1,2,3-thiadiazol-4-yl)benzyl]acetamidetrifluoroacetate

Yield: 0.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.773 min.)

MS (APCI+): 742 (M+H)

EXAMPLE 228(E)-3-(4-Methoxyphenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[3-(1,2,3-thiadiazol-4-yl)benzyl]-2-propenamidetrifluoroacetate

Yield: 3.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.803 min.)

MS (APCI+): 754 (M+H)

EXAMPLE 2292-(3-Fluorophenyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-N-[3-(1,2,3-thiadiazol-4-yl)benzyl]acetamidetrifluoroacetate

Yield: 1.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.791 min.)

MS (APCI+): 730 (M+H)

EXAMPLE 230N-(2-Oxo-2-{{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}[3-(1,2,3-thiadiazol-4-yl)benzyl]amino}ethyl)benzamidetrifluoroacetate

Yield: 1.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.695 min.)

MS (APCI+): 755 (M+H)

EXAMPLE 2312-(4-Bromophenyl)-N-(3-phenylpropyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 6.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.925 min.)

MS (APCI+): 734 (M+H), 736

EXAMPLE 2322-(3-Bromophenyl)-N-(3-phenylpropyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 7.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.829 min.)

MS (APCI+): 734 (M+H), 736

EXAMPLE 2332-(2-Bromophenyl)-N-(3-phenylpropyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 0.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.904 min.)

MS (APCI+): 734 (M+H), 736

EXAMPLE 234(E)-3-Phenyl-N-(3-phenylpropyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-2-propenamidetrifluoroacetate

Yield: 2.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.888 min.)

MS (APCI+): 668 (M+H)

EXAMPLE 2352-(Benzyloxy)-N-(3-phenylpropyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 4.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.844 min.)

MS (APCI+): 686 (M+H)

EXAMPLE 2364-Phenyl-N-(3-phenylpropyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}butanamidetrifluoroacetate

Yield: 4.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.933 min.)

MS (APCI+): 684 (M+H)

EXAMPLE 2373-(1H-Indol-3-yl)-N-(3-phenylpropyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}propanamidetrifluoroacetate

Yield: 1.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.855 min.)

MS (APCI+): 709 (M+H)

EXAMPLE 2382-(4-Methoxyphenyl)-N-(3-phenylpropyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 1.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.833 min.)

MS (APCI+): 686 (M+H)

EXAMPLE 2392-(3-Methoxyphenyl)-N-(3-phenylpropyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl)acetamidetrifluoroacetate

Yield: 2.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.831 min.)

MS (APCI+): 686 (M+H)

EXAMPLE 240(E)-3-(4-Methoxyphenyl)-N-(3-phenylpropyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}-2-propenamidetrifluoroacetate

Yield: 1.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.822 min.)

MS (APCI+): 698 (M+H)

EXAMPLE 2412-(3-Fluorophenyl)-N-(3-phenylpropyl)-N-{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 1.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.860 min.)

MS (APCI+): 674 (M+H)

EXAMPLE 242N-[2-Oxo-2-((3-phenylpropyl){[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)ethyl]benzamidetrifluoroacetate

Yield: 2.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.761 min.)

MS (APCI+): 699 (M+H)

EXAMPLE 243 Methyl4-[([2-(4-bromophenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 6.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.843 min.)

MS (APCI+): 764 (M+H), 766

EXAMPLE 244 Methyl4-[([2-(3-bromophenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 6.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.829 min.)

MS (APCI+): 764 (M+H), 766

EXAMPLE 245 Methyl4-[([2-(2-bromophenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 5.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.822 min.)

MS (APCI+): 764 (M+H), 766

EXAMPLE 246 Methyl4-[([(E)-3-phenyl-2-propenoyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 1.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.803 min.)

MS (APCI+): 698 (M+H)

EXAMPLE 247 Methyl4-[([2-(benzyloxy)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 1.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.760 min.)

MS (APCI+): 716 (M+H)

EXAMPLE 248 Methyl4-[([4-phenylbutanoyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 4.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.848 min.)

MS (APCI+): 714 (M+H)

EXAMPLE 249 Methyl4-[([3-(1H-indol-3-yl)propanoyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 3.3 mg

HPLC analysis (condition B): purity 100% (retention time: 1.784 min.)

MS (APCI+): 739 (M+H)

EXAMPLE 250 Methyl4-[([2-(4-methoxyphenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 5.2 mg

HPLC analysis (condition B): purity 100% (retention time: 1.753 min.)

MS (APCI+): 716 (M+H)

EXAMPLE 251 Methyl4-[([2-(3-methoxyphenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 4.5 mg

HPLC analysis (condition B): purity 100% (retention time: 1.765 min.)

MS (APCI+): 716 (M+H)

EXAMPLE 252 Methyl4-[([(E)-3-(4-methoxyphenyl)-2-propenoyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 5.8 mg

HPLC analysis (condition B): purity 100% (retention time: 1.793 min.)

MS (APCI+): 728 (M+H)

EXAMPLE 253 Methyl4-[([2-(3-fluorophenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 1.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.715 min.)

MS (APCI+): 704 (M+H)

EXAMPLE 254 Methyl4-[([2-(benzoylamino)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)methyl]benzoatetrifluoroacetate

Yield: 7.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.670 min.)

MS (APCI+): 729 (M+H)

EXAMPLE 255 Methyl6-[([2-(4-bromophenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 1.8 mg

HPLC analysis (condition B): purity 96% (retention time: 1.802 min.)

MS (APCI+): 744 (M+H), 746

EXAMPLE 256 Methyl6-[([2-(3-bromophenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 4.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.804 min.)

MS (APCI+): 744 (M+H), 746

EXAMPLE 257 Methyl6-[([2-(2-bromophenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.787 min.)

MS (APCI+): 744 (M+H), 746

EXAMPLE 258 Methyl6-[([(E)-3-phenyl-2-propenoyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 6.0 mg

HPLC analysis (condition B): purity 100% (retention time: 1.760 min.)

MS (APCI+): 678 (M+H)

EXAMPLE 259 Methyl6-[([2-(benzyloxy)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 4.7 mg

HPLC analysis (condition B): purity 100% (retention time: 1.725 min.)

MS (APCI+): 696 (M+H)

EXAMPLE 260 Methyl6-[([4-phenylbutanoyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 5.6 mg

HPLC analysis (condition B): purity 100% (retention time: 1.808 min.)

MS (APCI+): 694 (M+H)

EXAMPLE 261 Methyl6-[([3-(1H-indol-3-yl)propanoyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 0.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.739 min.)

MS (APCI+): 719 (M+H)

EXAMPLE 262 Methyl6-[([2-(4-methoxyphenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 5.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.718 min.)

MS (APCI+): 696 (M+H)

EXAMPLE 263 Methyl6-[([2-(3-methoxyphenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 3.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.721 min.)

MS (APCI+): 696 (M+H)

EXAMPLE 264 Methyl6-[([(E)-3-(4-methoxyphenyl)-2-propenoyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 3.9 mg

HPLC analysis (condition B): purity 100% (retention time: 1.769 min.)

MS (APCI+): 708 (M+H)

EXAMPLE 265 Methyl6-[([2-(3-fluorophenyl)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 5.4 mg

HPLC analysis (condition B): purity 100% (retention time: 1.7 min.)

MS (APCI+): 684 (M+H)

EXAMPLE 266 Methyl6-[([2-(benzoylamino)acetyl]{[3′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}amino)hexanoatetrifluoroacetate

Yield: 1.1 mg

HPLC analysis (condition B): purity 100% (retention time: 1.649 min.)

MS (APCI+): 709 (M+H)

The following compounds were produced in the same manner as in Example7.

EXAMPLE 2672-(4-Bromophenyl)-N-(4-hydroxyphenethyl)-N-{[2′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-4-yl]methyl}acetamidetrifluoroacetate

Yield: 3.5 mg

HPLC analysis (condition A): purity 76% (retention time: 3.408 min.)

MS (APCI−): 734 (M−H), 736

EXAMPLE 2682-(4-Bromophenyl)-N-(4-hydroxyphenethyl)-N-{[2′-({4-[2-(4-piperidinyl)ethyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 0.9 mg

HPLC analysis (condition A): purity 100% (retention time: 3.724 min.)

MS (APCI−): 720 (M−H), 722

EXAMPLE 2692-(4-Bromophenyl)-N-(4-hydroxyphenethyl)-N-{[2′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 0.9 mg

HPLC analysis (condition A): purity 98% (retention time: 3.819 min.)

MS (APCI−): 734 (M−H), 736

EXAMPLE 270N-(4-Hydroxyphenethyl)-2-(2-naphthyl)-N-{[2′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}acetamidetrifluoroacetate

Yield: 8.2 mg

HPLC analysis (condition A): purity 94% (retention time: 3.815 min.)

MS (APCI+): 708 (M+H)

EXAMPLE 271N-(4-Hydroxyphenethyl)-3-(1H-indol-3-yl)-N-{[2′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}propanamidetrifluoroacetate

Yield: 1.5 mg

HPLC analysis (condition A): purity 100% (retention time: 3.755 min.)

MS (APCI+): 711 (M+H)

EXAMPLE 272N-(4-Hydroxyphenethyl)-4-phenyl-N-{[2′-({4-[3-(4-piperidinyl)propyl]-1-piperidinyl}carbonyl)[1,1′-biphenyl]-3-yl]methyl}butanamidetrifluoroacetate

Yield: 4.7 mg

HPLC analysis (condition A): purity 100% (retention time: 3.826 min.)

MS (APCI+): 686 (M+H)

EXAMPLE 273N-{[2′-(1,4′-Bipiperidin-1′-ylcarbonyl)-1,1′-biphenyl-4-yl]methyl}-2-(4-bromophenyl)-N-[2-(4-hydroxyphenyl)ethyl]acetamidetrifluoroacetate

Yield: 19 mg

HPLC analysis (condition A): purity 85% (retention time: 3.413 min.)

MS (APCI+): 694 (M+H), 696

EXAMPLE 2744′-({[(4-Bromophenyl)acetyl][2-(4-hydroxyphenyl)ethyl]amino}methyl)-N-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 19 mg

HPLC analysis (condition A): purity 88% (retention time: 3.413 min.)

MS (APCI+): 640 (M+H), 642

EXAMPLE 2754′-({[(4-Bromophenyl)acetyl][2-(4-hydroxyphenyl)ethyl]amino}methyl)-N-[2-(dimethylamino)ethyl]-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 19 mg

HPLC analysis (condition A): purity 89% (retention time: 3.298 min.)

MS (APCI+): 614 (M+H), 616

EXAMPLE 276N-(2-Aminoethyl)-4′-({[(4-bromophenyl)acetyl][2-(4-hydroxyphenyl)ethyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 15 mg

HPLC analysis (condition A): purity 83% (retention time: 3.886 min.)

MS (APCI+): 586 (M+H), 588

EXAMPLE 277N-(3-Amino-2,2-dimethylpropyl)-4′-({[(4-bromophenyl)acetyl][2-(4-hydroxyphenyl)ethyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 17 mg

HPLC analysis (condition A): purity 77% (retention time: 4.071 min.)

MS (APCI+): 628 (M+H), 630

EXAMPLE 278N-{[2′-(1,4′-Bipiperidin-1′-ylcarbonyl)-1,1′-biphenyl-4-yl]methyl}-N-[2-(4-hydroxyphenyl)ethyl]-N-(phenylacetyl)glycineamidetrifluoroacetate

Yield: 16 mg

HPLC analysis (condition A): purity 72% (retention time: 2.930 min.)

MS (APCI+): 673 (M+H)

EXAMPLE 279N-[2-(Dimethylamino)ethyl]-4′-({[2-(4-hydroxyphenyl)ethyl][N-(phenylacetyl)glycyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 22 mg

HPLC analysis (condition A): purity 89% (retention time: 2.819 min.)

MS (APCI+): 593 (M+H)

EXAMPLE 280N-{[2′-(1,4′-Bipiperidin-1′-ylcarbonyl)-1,1′-biphenyl-3-yl]methyl}-2-(4-bromophenyl)-N-[2-(4-hydroxyphenyl)ethyl]acetamidetrifluoroacetate

Yield: 19 mg

HPLC analysis (condition A): purity 86% (retention time: 3.327 min.)

MS (APCI+): 694 (M+H), 696

EXAMPLE 2813′-({[(4-Bromophenyl)acetyl][2-(4-hydroxyphenyl)ethyl]amino}methyl)-N-[2-(dimethylamino)ethyl]-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 15 mg

HPLC analysis (condition A): purity 86% (retention time: 3.275 min.)

MS (APCI+): 614 (M+H), 616

EXAMPLE 282N-{[2′-(1,4′-Bipiperidin-1′-ylcarbonyl)-1,1′-biphenyl-3-yl]methyl}-N-[2-(4-hydroxyphenyl)ethyl]-N-(phenylacetyl)glycineamidetrifluoroacetate

Yield: 21 mg

HPLC analysis (condition A): purity 85% (retention time: 3.041 min.)

MS (APCI+): 673 (M+H)

EXAMPLE 283N-[2-(Dimethylamino)ethyl]-3′-({[2-(4-hydroxyphenyl)ethyl][N-(phenylacetyl)glycyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 12 mg

HPLC analysis (condition A): purity 90% (retention time: 2.965 min.)

MS (APCI+): 593 (M+H)

EXAMPLE 284N-(2-Aminoethyl)-3′-({[(4-bromophenyl)acetyl][2-(4-hydroxyphenyl)ethyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 6.4 mg

HPLC analysis (condition A): purity 100% (retention time: 3.580 min.)

MS (APCI+): 586 (M+H), 588

EXAMPLE 285N-(3-Amino-2,2-dimethylpropyl)-3′-({[(4-bromophenyl)acetyl][2-(4-hydroxyphenyl)ethyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 1.8 mg

HPLC analysis (condition A): purity 98% (retention time: 3.597 min.)

MS (APCI+): 628 (M+H), 630

EXAMPLE 2862-({[3′-({[(4-Bromophenyl)acetyl][2-(4-hydroxyphenyl)ethyl]amino}methyl)-1,1′-biphenyl-2-yl]carbonyl}amino)ethylimidothiocarbamate trifluoroacetate

Yield: 9.9 mg

HPLC analysis (condition A): purity 99% (retention time: 3.806 min.)

MS (APCI+): 646 (M+H), 648

EXAMPLE 287N-{[2′-(1,4′-Bipiperidin-1′-ylcarbonyl)-1,1′-biphenyl-3-yl]methyl)-N-[2-(4-hydroxyphenyl)ethyl]-4-phenylbutanamidetrifluoroacetate

Yield: 2.4 mg

HPLC analysis (condition A): purity 98% (retention time: 3.711 min.)

MS (APCI+): 644 (M+H)

EXAMPLE 288N-(2-Aminoethyl)-3′-({[(4-chlorophenyl)acetyl][2-(4-hydroxyphenyl)ethyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 15 mg

HPLC analysis (condition A): purity 91% (retention time: 3.462 min.)

MS (APCI+): 542 (M+H)

EXAMPLE 289N-(2-Aminoethyl)-3′-([[2-(4-chlorophenyl)ethyl][2-naphthylacetyl)amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 11 mg

HPLC analysis (condition A): purity 100% (retention time: 3.533 min.)

MS (APCI+): 558 (M+H)

EXAMPLE 290N-(2-Aminoethyl)-3′-([[2-(4-hydroxyphenyl)ethyl][3-(1H-indol-3-yl)propanoyl]amino]methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 1.5 mg

HPLC analysis (condition A): purity 100% (retention time: 3.490 min.)

MS (APCI+): 561 (M+H)

EXAMPLE 291N-(2-Aminoethyl)-3′-{[[2-(4-hydroxyphenyl)ethyl][4-phenylbutanoyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 19 mg

HPLC analysis (condition A): purity 90% (retention time: 3.517 min.)

MS (APCI+): 536 (M+H)

EXAMPLE 292N-(2-Aminoethyl)-3′-({[(2E)-3-(2-fluorophenyl)-2-propenoyl][2-(4-hydroxyphenyl)ethyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 19 mg

HPLC analysis (condition A): purity 90% (retention time: 3.455 min.)

MS (APCI+): 538 (M+H)

EXAMPLE 293N-(2-Aminoethyl)-3′-{[[2-(4-hydroxyphenyl)ethyl]({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 18 mg

HPLC analysis (condition A): purity 86% (retention time: 3.575 min.)

MS (APCI+): 577 (M+H)

EXAMPLE 294N-(6-Aminohexyl)-3′-([[2-(4-hydroxyphenyl)ethyl][3-(1H-indol-3-yl)propanoyl]amino]methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 1.4 mg

HPLC analysis (condition A): purity 99% (retention time: 3.500 min.)

MS (APCI+): 617 (M+H)

EXAMPLE 295N-(6-Aminohexyl)-3′-{[[2-(4-hydroxyphenyl)ethyl]([{3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 4.2 mg

HPLC analysis (condition A): purity 100% (retention time: 3.739 min.)

MS (APCI+): 633 (M+H)

EXAMPLE 296N-{[4-(Aminoethyl)cyclohexyl]methyl}-3′-([[2-(4-hydroxyphenyl)ethyl][3-(1H-indol-3-yl)propanoyl]amino]methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 1.0 mg

HPLC analysis (condition A): purity 100% (retention time: 3.540 min.)

MS (APCI+): 643 (M+H)

EXAMPLE 297N-{[4-(Aminoethyl)cyclohexyl]methyl)-3′-{[[2-(4-hydroxyphenyl)ethyl]({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 6.0 mg

HPLC analysis (condition A): purity 100% (retention time: 3.776 min.)

MS (APCI+): 659 (M+H)

EXAMPLE 298N-{[2′-(1,4′-Bipiperidin-1′-ylcarbonyl)-1,1′-biphenyl-3-yl]methyl}-N-[2-(4-hydroxyphenyl)ethyl]-4-(2-thienyl)butanamidetrifluoroacetate

Yield: 4.0 mg

HPLC analysis (condition A): purity 100% (retention time: 3.905 min.)

MS (APCI+): 650 (M+H)

EXAMPLE 299N-{[2′-(1,4′-Bipiperidin-1′-ylcarbonyl)-1,1′-biphenyl-3-yl]methyl)-N-[2-(4-hydroxyphenyl)ethyl]-4-(1-naphthyloxy)acetamidetrifluoroacetate

Yield: 12 mg

HPLC analysis (condition A): purity 93% (retention time: 4.050 min.)

MS (APCI+): 682 (M+H)

EXAMPLE 300(2E)-N-{[2′-(1,4′-Bipiperidin-1′-ylcarbonyl)-1,1′-biphenyl-3-yl]methyl}-3-(3-fluorophenyl)-N-[2-(4-hydroxyphenyl)ethyl]-2-propenamidetrifluoroacetate

Yield: 10 mg

HPLC analysis (condition A): purity 100% (retention time: 3.958 min.)

MS (APCI+): 646 (M+H)

The following compounds were produced in the same manner as in Example71.

EXAMPLE 301N-(2-Aminoethyl)-3′-({[(2E)-3-(4-fluorophenyl)-2-propenoyl](1-naphthylmethyl)amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 15 mg HPLC analysis (condition A): purity 81% (retention time:3.674 min.)

MS (APCI+): 558 (M+H)

EXAMPLE 302N-(2-Aminoethyl)-3′-[((1-naphthylmethyl){(2E)-3-[3-(trifluoromethyl)phenyl]-2-propenoyl}amino)methyl]-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 14 mg

HPLC analysis (condition A): purity 84% (retention time: 3.882 min.)

MS (APCI+): 608 (M+H)

EXAMPLE 303N-(2-Aminoethyl)-3′-({(1-naphthylmethyl)[N-(phenylacetyl)glycyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 15 mg

HPLC analysis (condition A): purity 94% (retention time: 3.695 min.)

MS (APCI+): 585 (M+H)

EXAMPLE 304N-(2-Aminoethyl)-3′-{[(N-benzoylglycyl)(1-naphthylmethyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 16 mg

HPLC analysis (condition A): purity 89% (retention time: 3.848 min.)

MS (APCI+): 571 (M+H)

EXAMPLE 305N-(2-Aminoethyl)-3′-{[[2-(1H-indol-3-yl)ethyl](4-phenylbutanoyl)amino]methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 1.4 mg

HPLC analysis (condition A): purity 100% (retention time: 3.513 min.)

MS (APCI+): 559 (M+H)

EXAMPLE 306N-(2-Aminoethyl)-3′-{[[2-(1H-indol-3-yl)ethyl]{4-(2-thienyl)butanoyl}amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 1.3 mg

HPLC analysis (condition A): purity 100% (retention time: 3.400 min.)

MS (APCI+): 565 (M+H)

EXAMPLE 307N-(2-Aminoethyl)-3′-{{[2-(1H-indol-3-yl)ethyl][3-(1H-indol-3-yl)propanoyl]amino}methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 1.1 mg

HPLC analysis (condition A): purity 98% (retention time: 2.822 min.)

MS (APCI+): 584 (M+H)

EXAMPLE 308N-(2-Aminoethyl)-3′-({(3,3-diphenylpropyl)[3-(1H-indol-3-yl)propanoyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 1.3 mg

HPLC analysis (condition A): purity 97% (retention time: 3.621 min.)

MS (APCI+): 635 (M+H)

EXAMPLE 309 Methyl{[(2′-{[(2-aminoethyl)amino]carbonyl)-1,1′-biphenyl-3-yl)methyl][(4-bromophenyl)acetyl]amino}(phenyl)acetatetrifluoroacetate

Yield: 3.7 mg

HPLC analysis (condition A): purity 98% (retention time: 4.935 min.)

MS (APCI+): 614 (M+H), 616

EXAMPLE 310 Methyl[[(2′-{[(2-aminoethyl)amino]carbonyl}-1,1′-biphenyl-3-yl)methyl][(4-phenylbutanoyl)amino](phenyl)acetatetrifluoroacetate

Yield: 1.3 mg

HPLC analysis (condition A): purity 87% (retention time: 3.337 min.)

MS (APCI+): 564 (M+H) EXAMPLE 311 Methyl{[(2′-{[(2-aminoethyl)amino]carbonyl}-1,1′-biphenyl-3-yl)methyl][N-(phenylacetyl)glycyl]amino}(phenyl)acetatetrifluoroacetate

Yield: 2.5 mg

HPLC analysis (condition A): purity 98% (retention time: 3.018 min.)

MS (APCI+): 593 (M+H)

EXAMPLE 312N-(2-Aminoethyl)-3′-{[(1-benzylpiperidin-4-yl)(4-phenylbutanoyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 21 mg

HPLC analysis (condition A): purity 97% (retention time: 2.863 min.)

MS (APCI+): 589 (M+H)

EXAMPLE 313N-(2-Aminoethyl)-3′-{[(1-benzylpiperidin-4-yl){4-(2-thienyl)butanoyl}amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 2.6 mg

HPLC analysis (condition A): purity 100% (retention time: 2.825 min.)

MS (APCI+): 595 (M+H)

EXAMPLE 314N-(2-Aminoethyl)-3′-{[[(2E)-3-(4-fluorophenyl)-2-propenoyl](4-phenoxyphenyl)amino]methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 18 mg

HPLC analysis (condition A): purity 95% (retention time: 3.339 min.)

MS (APCI+): 586 (M+H)

EXAMPLE 315N-(2-Aminoethyl)-3′-({{4-[(E)-2-(4-methoxyphenyl)ethenyl]phenyl}{N-(phenylacetyl)glycyl}amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 2.3 mg

HPLC analysis (condition A): purity 100% (retention time: 3.455 min.)

MS (APCI+): 653 (M+H)

EXAMPLE 316N-(2-Aminoethyl)-3′-({(4-benzoylphenyl)[(benzyloxy)acetyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 20 mg

HPLC analysis (condition A): purity 84% (retention time: 3.807 min.)

MS (APCI+): 598 (M+H)

EXAMPLE 317 EthylN-[(2′-{[(2-aminoethyl)amino]carbonyl}-1,1′-biphenyl-3-yl)methyl]-N-[(4-bromophenyl)acetyl]tyrosinatetrifluoroacetate

Yield: 4.1 mg

HPLC analysis (condition A): purity 99% (retention time: 2.818 min.)

MS (APCI+): 658 (M+H), 660

EXAMPLE 318 EthylN-[(2′-{[(2-aminoethyl)amino]carbonyl}-1,1′-biphenyl-3-yl)methyl]-N-[(4-methoxyphenyl)acetyl]tyrosinatetrifluoroacetate

Yield: 1.9 mg

HPLC analysis (condition A): purity 89% (retention time: 3.044 min.)

MS (APCI+): 610 (M+H)

EXAMPLE 319 EthylN-(phenylacetyl)glycyl-N-[(2′-{[(2-aminoethyl)amino]carbonyl}-1,1′-biphenyl-3-yl)methyl]tyrosinatetrifluoroacetate

Yield: 4.3 mg

HPLC analysis (condition A): purity 99% (retention time: 2.987 min.)

MS (APCI+): 637 (M+H)

EXAMPLE 320 EthylN-[(2′-{[(2-aminoethyl)amino]carbonyl}-1,1′-biphenyl-3-yl)methyl]-N-[(2-naphthylacetyl)tyrosinatetrifluoroacetate

Yield: 3.4 mg

HPLC analysis (condition A): purity 88% (retention time: 3.217 min.)

MS (APCI+): 630 (M+H)

EXAMPLE 3213′-{[(4-Aminobutanoyl)(1-naphthylmethyl)amino]methyl}-N-(2-aminoethyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 18 mg

HPLC analysis (condition A): purity 95% (retention time: 2.643 min.)

MS (APCI+): 495 (M+H)

EXAMPLE 322N-[(2′-{[(2-Aminoethyl)amino]carbonyl}-1,1′-biphenyl-3-yl)methyl]-N-(1-naphthylmethyl)piperidine-4-carboxamidetrifluoroacetate

Yield: 27 mg

HPLC analysis (condition A): purity 93% (retention time: 2.649 min.)

MS (APCI+): 521 (M+H)

EXAMPLE 323N-(2-Aminoethyl)-3′-{[{[4-(aminomethyl)cyclohexyl]carbonyl}(1-naphthylmethyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 11 mg

HPLC analysis (condition A): purity 9% (retention time: 2.740 min.)

MS (APCI+): 549 (M+H)

EXAMPLE 324N-(2-Aminoethyl)-3′-{[[4-({[amino(imino)methyl]amino}methyl)benzoyl](1-naphthylmethyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 7.1 mg

HPLC analysis (condition A): purity 80% (retention time: 2.789 min.)

MS (APCI+): 585 (M+H)

EXAMPLE 325N-(2-Aminoethyl)-3′-{[[3-({[amino(imino)methyl]amino}methyl)benzoyl](1-naphthylmethyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 9.6 mg

HPLC analysis (condition A): purity 98% (retention time: 2.796 min.)

MS (APCI+): 585 (M+H)

EXAMPLE 326N-(2-Aminoethyl)-3′-{[[5-{[amino(imino)methyl]amino}pentanoyl)(1-naphthylmethyl)amino]methyl]-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 26 mg

HPLC analysis (condition A): purity 91% (retention time: 2.763 min.)

MS (APCI+): 551 (M+H)

EXAMPLE 327N-(2-Aminoethyl)-3′-{[{[4-({[amino(imino)methyl]amino}methyl)cyclohexyl]carbonyl}(1-naphthylmethyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 7.4 mg

HPLC analysis (condition A): purity 98% (retention time: 2.850 min.)

MS (APCI+): 591 (M+H)

EXAMPLE 328N-(2-Aminoethyl)-3′-{[[4-(aminosulfonyl)benzoyl](1-naphthylmethyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 8.5 mg

HPLC analysis (condition A): purity 95% (retention time: 3.062 min.)

MS (APCI+): 593 (M+H)

EXAMPLE 3293′-{[{[2-(Aminocarbonyl)phenoxy]acetyl}(1-naphthylmethyl)amino]methyl}-N-(2-aminoethyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 22 mg

HPLC analysis (condition A): purity 96% (retention time: 3.211 min.)

MS (APCI+): 587 (M+H)

EXAMPLE 330N-(2-Aminoethyl)-3′-{[(1-naphthylmethyl)(tyrosyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 21 mg

HPLC analysis (condition A): purity 94% (retention time: 2.749 min.)

MS (APCI+): 573 (M+H)

EXAMPLE 331N-(2-Aminoethyl)-3′-{[[2-(4-methoxyphenyl)ethyl](tyrosyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 19 mg

HPLC analysis (condition A): purity 94% (retention time: 2.615 min.)

MS (APCI+): 567 (M+H)

EXAMPLE 332N-(2-Aminoethyl)-3′-{[[2-(2,4-dichlorophenyl)ethyl](tyrosyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 22 mg

HPLC analysis (condition A): purity 94% (retention time: 2.888 min.)

MS (APCI+): 605 (M+H)

EXAMPLE 333N-(2-Aminoethyl)-3′-{[(3,3-diphenylpropyl)(tyrosyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 21 mg

HPLC analysis (condition A): purity 97% (retention time: 2.950 min.)

MS (APCI+): 627 (M+H)

EXAMPLE 334N-(2-Aminoethyl)-3′-{[(4-phenylbutyl)(tyrosyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 9.7 mg

HPLC analysis (condition A): purity 96% (retention time: 2.833 min.)

MS (APCI+): 565 (M+H)

EXAMPLE 335N-(2-Aminoethyl)-3′-{[{3-[methyl(phenyl)amino]propyl}(tyrosyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 10 mg

HPLC analysis (condition A): purity 96% (retention time: 2.096 min.)

MS (APCI+): 580 (M+H)

EXAMPLE 336N-(2-Aminoethyl)-3′-({[4-({[amino(imino)methyl]amino}methyl)benzoyl][2-(2,4-dichlorophenyl)ethyl]amino}methyl)-1,1′-biphenyl-3-carboxamidetrifluoroacetate

Yield: 25 mg

HPLC analysis (condition A): purity 87% (retention time: 2.953 min.)

MS (APCI+): 617 (M+H)

EXAMPLE 337N-(2-Aminoethyl)-3′-{[[4-({[amino(imino)methyl]amino}methyl)benzoyl](1-naphthylmethyl)amino]methyl}-1,1′-biphenyl-3-carboxamidetrifluoroacetate

Yield: 2.1 mg

HPLC analysis (condition A): purity 98% (retention time: 2.860 min.)

MS (APCI+): 585 (M+H)

EXAMPLE 338N-(2-Aminoethyl)-3′-{[[4-({[amino(imino)methyl]amino}methyl)benzoyl](4-phenylbutyl)amino]methyl}-1,1′-biphenyl-3-carboxamidetrifluoroacetate

Yield: 11 mg

HPLC analysis (condition A): purity 99% (retention time: 2.927 min.)

MS (APCI+): 577 (M+H)

EXAMPLE 339N-(2-Aminoethyl)-4′-{[[4-({[amino(imino)methyl]amino}methyl)benzoyl](3,3-diphenylpropyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 11 mg

HPLC analysis (condition A): purity 98% (retention time: 2.977 min.)

MS (APCI+): 639 (M+H)

EXAMPLE 340N-(2-Aminoethyl)-4′-{[[(benzyloxy)acetyl](4-phenoxyphenyl)amino]methyl}-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 17 mg

HPLC analysis (condition A): purity 87% (retention time: 3.485 min.)

MS (APCI+): 586 (M+H)

EXAMPLE 341N-(2-Aminoethyl)-4′-({{4-[(E)-2-(4-methoxyphenyl)ethenyl]phenyl}[N-(phenylacetyl)glycyl]amino}methyl)-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 2.0 mg

HPLC analysis (condition A): purity 99% (retention time: 3.462 min.)

MS (APCI+): 653 (M+H)

EXAMPLE 342N-(2-Aminoethyl)-4′-[((N-benzoylglycyl){4-[(E)-2-(4-methoxyphenyl)ethenyl]phenyl}amino)methyl]-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 1.5 mg

HPLC analysis (condition A): purity 99% (retention time: 3.448 min.)

MS (APCI+): 639 (M+H)

EXAMPLE 343N-(2-Aminoethyl)-4′-[([(benzyloxy)acetyl]{4-[(E)-2-(4-methoxyphenyl)ethenyl]phenyl}amino)methyl]-1,1′-biphenyl-2-carboxamidetrifluoroacetate

Yield: 1.8 mg

HPLC analysis (condition A): purity 100% (retention time: 3.604 min.)

MS (APCI+): 626 (M+H)

The compounds obtained in the Examples above, compounds obtained byanalogous methods to those in the Examples above, and results of massspectra (MS) thereof are shown below.

R    R²  

548 (M + H) 546 (M + H) 547 (M + H)

614 (M + H), 616 612 (M + H) 614 640 (M + H) 642

566 (M + H) 564 (M + H) 592 (M + H)

564 (M + H) 562 (M + H) 590 (M + H)

579 (M + H) 577 (M + H) 605 (M + H)

589 (M + H) 587 (M + H) 615 (M + H)

575 (M + H) 573 (M + H) 601 (M + H)

516 (M + H) 514 (M + H) 542 (M + H) R         R²  .     

    

574 (M + H) 590 (M + H) 574 (M + H)

640 (M + H) 642 656 (M + H) 658 640 (M + H) 642

592 (M + H) 608 (M + H) 592 (M + H)

590 (M + H) 606 (M + H) 590 (M + H)

605 (M + H) 621 (M + H) 605 (M + H)

615 (M + H) 631 (M + H) 615 (M + H)

601 (M + H) 617 (M + H) 601 (M + H)

542 (M + H) 558 (M + H) 542 (M + H) R      R²   

  

585 (M + H) 617 (M + H) 628 (M + H)

651 (M + H) 653 683 (M + H) 685 694 (M + H) 696

603 (M + H) 635 (M + H) 646 (M + H)

601 (M + H) 633 (M + H) 644 (M + H)

626 (M + H) 648 (M + H) 659 (M + H)

626 (M + H) 658 (M + H) 669 (M + H)

612 (M + H) 644 (M + H) 655 (M + H)

553 (M + H) 585 (M + H) 596 (M + H) R         R²     

    

568 (M + H) 574 (M + H) 670 (M + H)

638 (M + H) 636 640 (M + H) 642 736 (M + H) 738

586 (M + H) 592 (M + H) 688 (M + H)

584 (M + H) 590 (M + H) 686 (M + H)

599 (M + H) 605 (M + H) 701 (M + H)

609 (M + H) 615 (M + H) 711 (M + H)

595 (M + H) 601 (M + H) 697 (M + H)

536 (M + H) 542 (M + H) 638 (M + H) R     R²  

538 (M + H) 536 (M + H) 564 (M + H)

549 (M + H) 547 (M + H) 575 (M + H)

614 (M + H) 616 612 (M + H) 614 640 (M + H) 642

614 (M + H) 616 612 (M + H) 614 640 (M + H) 642

569 (M + H) 567 (M + H) 595 (M + H)

566 (M + H) 564 (M + H) 592 (M + H)

578 (M + H) 576 (M + H) 604 (M + H)

626 (M + H) 628 624 (M + H) 626 652 (M + H) 654 R        R²     

    

564 (M + H) 580 (M + H) 564 (M + H)

575 (M + H) 591 (M + H) 575 (M + H)

640 (M + H) 642 656 (M + H) 658 640 (M + H) 642

640 (M + H) 642 656 (M + H) 658 640 (M + H) 642

595 (M + H) 611 (M + H) 595 (M + H)

592 (M + H) 608 (M + H) 592 (M + H)

604 (M + H) 620 (M + H) 604 (M + H)

652 (M + H) 654 668 (M + H) 670 652 (M + H) 654 R     R₂   

  

575 (M + H) 607 (M + H) 618 (M + H)

586 (M + H) 618 (M + H) 629 (M + H)

651 (M + H) 653 683 (M + H) 685 694 (M + H) 696

651 (M + H) 653 683 (M + H) 685 694 (M + H) 696

606 (M + H) 638 (M + H) 649 (M + H)

603 (M + H) 635 (M + H) 646 (M + H)

615 (M + H) 647 (M + H) 658 (M + H)

663 (M + H) 665 695 (M + H) 697 706 (M + H) 708 R         R₂      

     

558 (M + H) 564 (M + H) 660 (M + H)

569 (M + H) 575 (M + H) 671 (M + H)

634 (M + H) 636 640 (M + H) 642 736 (M + H) 738

634 (M + H) 636 640 (M + H) 642 736 (M + H) 738

589 (M + H) 595 (M + H) 691 (M + H)

586 (M + H) 592 (M + H) 688 (M + H)

598 (M + H) 604 (M + H) 700 (M + H)

646 (M + H) 648 652 (M + H) 654 748 (M + H) 750 R    R²

  

520 (M + H) 534 (M + H) 548 (M + H)

586 (M + H) 588 600 (M + H) 602 614 (M + H) 616

538 (M + H) 552 (M + H) 566 (M + H)

536 (M + H) 550 (M + H) 564 (M + H)

551 (M + H) 565 (M + H) 579 (M + H)

561 (M + H) 575 (M + H) 589 (M + H)

547 (M + H) 561 (M + H) 575 (M + H)

488 (M + H) 502 (M + H) 516 (M + H) R    R²

  

562 (M + H) 576 (M + H) 602 (M + H)

628 (M + H) 630 642 (M + H) 644 668 (M + H) 670

580 (M + H) 594 (M + H) 620 (M + H)

578 (M + H) 592 (M + H) 618 (M + H)

593 (M + H) 607 (M + H) 633 (M + H)

603 (M + H) 617 (M + H) 643 (M + H)

589 (M + H) 603 (M + H) 629 (M + H)

530 (M + H) 544 (M + H) 570 (M + H) R       R²    

   

602 (M + H) 574 (M + H) 574 (M + H)

668 (M + H) 670 640 (M + H) 642 640 (M + H) 642

620 (M + H) 592 (M + H) 592 (M + H)

618 (M + H) 590 (M + H) 590 (M + H)

633 (M + H) 605 (M + H) 605 (M + H)

643 (M + H) 615 (M + H) 615 (M + H)

629 (M + H) 601 (M + H) 601 (M + H)

570 (M + H) 542 (M + H) 542 (M + H) R       R²

 

574 (M + H) 577 (M + H)

640 (M + H) 642 643 (M + H) 645

592 (M + H) 595 (M + H)

590 (M + H) 593 (M + H)

605 (M + H) 608 (M + H)

615 (M + H) 618 (M + H)

601 (M + H) 604 (M + H)

542 (M + H) 545 (M + H) R    R²

  

510 (M + H) 524 (M + H) 538 (M + H)

521 (M + H) 535 (M + H) 549 (M + H)

586 (M + H) 588 600 (M + H) 602 614 (M + H) 616

586 (M + H) 588 600 (M + H) 602 614 (M + H) 616

541 (M + H) 555 (M + H) 569 (M + H)

538 (M + H) 552 (M + H) 566 (M + H)

550 (M + H) 564 (M + H) 578 (M + H)

598 (M + H) 600 612 (M + H) 614 626 (M + H) 628 R    R²

  

552 (M + H) 566 (M + H) 592 (M + H)

563 (M + H) 577 (M + H) 603 (M + H)

628 (M + H) 630 642 (M + H) 644 668 (M + H) 670

628 (M + H) 630 642 (M + H) 644 668 (M + H) 670

583 (M + H) 597 (M + H) 623 (M + H)

580 (M + H) 594 (M + H) 620 (M + H)

592 (M + H) 606 (M + H) 632 (M + H)

640 (M + H) 642 654 (M + H) 656 680 (M + H) 682 R        R²    

   

592 (M + H) 564 (M + H) 564 (M + H)

603 (M + H) 675 (M + H) 675 (M + H)

668 (M + H) 670 640 (M + H) 642 640 (M + H) 642

668 (M + H) 670 640 (M + H) 642 640 (M + H) 642

623 (M + H) 595 (M + H) 595 (M + H)

620 (M + H) 592 (M + H) 592 (M + H)

632 (M + H) 604 (M + H) 604 (M + H)

680 (M + H) 682 652 (M + H) 654 652 (M + H) 654 R       R²

 

564 (M + H) 567 (M + H)

675 (M + H) 678 (M + H)

640 (M + H) 642 643 (M + H) 645

640 (M + H) 642 643 (M + H) 645

595 (M + H) 598 (M + H)

592 (M + H) 595 (M + H)

604 (M + H) 607 (M + H)

652 (M + H) 654 655 (M + H) 657

R³         R²

   

    

   

581 (M − H) 567 (M − H) 503 (M − H) 523 (M − H)

647 (M − H) 649 633 (M − H) 635 571 (M + H) 573 589 (M − H) 591

599 (M − H) 585 (M − H) 523 (M + H) 541 (M − H)

597 (M − H) 583 (M − H) 521 (M + H) 539 (M − H)

612 (M − H) 598 (M − H) 536 (M + H) 554 (M − H)

622 (M − H) 608 (M − H) 544 (M − H) 564 (M − H)

608 (M − H) 694 (M − H) 530 (M − H) 550 (M − H)

571 (M − H) 557 (M − H) 495 (M + H) 513 (M − H) R³         R²      

   

   

508 (M − H) 574 (M + H) 580 (M − H) 582 516 (M − H)

574 (M − H) 576 640 (M + H) 642 648 (M + H) 650 582 (M − H) 584

526 (M − H) 592 (M + H) 598 (M − H) 600 534 (M − H)

524 (M − H) 590 (M + H) 596 (M − H) 598 532 (M − H)

539 (M − H) 605 (M + H) 613 (M + H) 615 547 (M − H)

549 (M − H) 615 (M + H) 623 (M + H) 625 557 (M − H)

535 (M − H) 601 (MH) 608 (M + H) 610 543 (M − H)

498 (M − H) 564 (M + H) 572 (M + H) 574 506 (M − H) R³        R²

   

    

582 (M − H) 568 (M − H) 506 (M + H)

647 (M − H) 649 633 (M − H) 635 571 (M + H) 573

647 (M − H) 649 633 (M − H) 635 571 (M + H) 573

611 (M − H) 597 (M − H) 535 (M + H)

599 (M − H) 585 (M − H) 521 (M − H)

585 (M − H) 571 (M − H) 507 (M − H)

597 (M − H) 583 (M − H) 519 (M − H)

599 (M − H) 585 (M − H) 521 (M − H) R³         R²    

     

524 (M − H) 509 (M − H) 575 (M + H)

589 (M − H) 591 576 (M + H) 578 640 (M + H) 642

589 (M − H) 591 574 (M − H) 576 640 (M + H) 642

553 (M − H) 538 (M − H) 604 (M + H)

541 (M − H) 526 (M − H) 592 (M + H)

527 (M − H) 512 (M − H) 578 (M + H)

539 (M − H) 524 (M − H) 590 (M + H)

541 (M − H) 526 (M − H) 592 (M + H) R³      R²

581 (M − H) 583 517 (M − H)

646 (M + H) 648 582 (M − H) 584

646 (M + H) 648 582 (M − H) 584

611 (M − H) 613 546 (M − H)

598 (M − H) 600 534 (M − H)

586 (M + H) 588 520 (M − H)

596 (M − H) 598 532 (M − H)

598 (M − H) 600 534 (M − H)

R³     R²

 

703 (M + H) 705 689 (M + H) 691 625 (M + H) 627

703 (M + H) 705 689 (M + H) 691 625 (M + H) 627

703 (M + H) 705 689 (M + H) 691 625 (M + H) 627

637 (M + H) 623 (M + H) 559 (M + H)

655 (M + H) 641 (M + H) 677 (M + H)

653 (M + H) 639 (M + H) 575 (M + H)

678 (M + H) 664 (M + H) 600 (M + H)

655 (M + H) 641 (M + H) 577 (M + H)

655 (M + H) 639 (M − H) 577 (M + H)

667 (M + H) 653 (M + H) 589 (M + H)

643 (M + H) 629 (M + H) 565 (M + H)

668 (M + H) 654 (M + H) 590 (M + H) R³          R²       

      

630 (M + H) 632 694 (M + H) 696 638 (M + H) 640 668 (M + H) 670

630 (M + H) 632 694 (M + H) 696 638 (M + H) 640 668 (M + H) 670

630 (M + H) 632 694 (M + H) 696 638 (M + H) 640 668 (M + H) 670

564 (M + H) 628 (M + H) 572 (M + H) 602 (M + H)

582 (M + H) 646 (M + H) 590 (M + H) 620 (M + H)

580 (M + H) 644 (M + H) 588 (M + H) 618 (M + H)

605 (M + H) 669 (M + H) 613 (M + H) 643 (M + H)

582 (M + H) 646 (M + H) 590 (M + H) 620 (M + H)

582 (M + H) 646 (M + H) 590 (M + H) 620 (M + H)

594 (M + H) 658 (M + H) 602 (M + H) 632 (M + H)

570 (M + H) 634 (M + H) 578 (M + H) 608 (M + H)

595 (M + H) 659 (M + H) 603 (M + H) 633 (M + H) R³         R²      

     

648 (M + H) 650 652 (M − H) 654 632 (M − H) 634

648 (M + H) 650 652 (M − H) 654 632 (M − H) 634

648 (M + H) 650 652 (M − H) 654 632 (M − H) 634

582 (M + H) 598 (M + H) 566 (M − H)

600 (M + H) 604 (M − H) 584 (M − H)

598 (M + H) 602 (M − H) 582 (M − H)

623 (M + H) 627 (M − H) 607 (M − H)

600 (M + H) 604 (M − H) 584 (M − H)

600 (M + H) 604 (M − H) 584 (M − H)

612 (M + H) 616 (M − H) 596 (M − H)

588 (M + H) 592 (M − H) 572 (M − H)

613 (M + H) 617 (M − H) 597 (M − H)

R³     R²

799 (M + H) 801 783 (M + H) 785 721 (M + H) 723

797 (M − H) 799 783 (M + H) 785 721 (M + H) 723

797 (M − H) 799 783 (M + H) 785 721 (M + H) 723

731 (M − H) 717 (M − H) 655 (M + H)

751 (M + H) 735 (M − H) 673 (M + H)

747 (M − H) 733 (M − H) 671 (M + H)

772 (M − H) 758 (M − H) 694 (M − H)

749 (M − H) 735 (M − H) 673 (M + H)

749 (M − H) 735 (M − H) 673 (M + H)

761 (M − H) 747 (M − H) 685 (M + H)

737 (M − H) 723 (M − H) 661 (M + H)

762 (M − H) 748 (M − H) 686 (M + H) R³    R²

726 (M + H) 728

726 (M + H) 728

726 (M + H) 728

660 (M + H)

678 (M + H)

676 (M + H)

701 (M + H)

678 (M + H)

678 (M + H)

690 (M + H)

666 (M + H)

691 (M + H)

R³          R²

      

790 (M + H) 792 734 (M + H) 736 764 (M + H) 766

790 (M + H) 792 734 (M + H) 736 764 (M + H) 766

790 (M + H) 792 734 (M + H) 736 764 (M + H) 766

724 (M + H) 668 (M + H) 698 (M + H)

742 (M + H) 686 (M + H) 716 (M + H)

740 (M + H) 684 (M + H) 714 (M + H)

765 (M + H) 709 (M + H) 739 (M + H)

742 (M + H) 686 (M + H) 716 (M + H)

742 (M + H) 686 (M + H) 716 (M + H)

754 (M + H) 698 (M + H) 728 (M + H)

730 (M + H) 674 (M + H) 704 (M + H)

755 (M + H) 699 (M + H) 729 (M + H) R³    R²

744 (M + H) 746

744 (M + H) 746

744 (M + H) 746

678 (M + H)

696 (M + H)

694 (M + H)

719 (M + H)

696 (M + H)

696 (M + H)

708 (M + H)

684 (M + H)

709 (M + H)

MS (AP- R CI+)

640(M +H), 642

694(M +H), 696

614(M +H), 616

668(M +H), 670

726(M +H), 728

586(M +H), 588

600(M +H), 622

614(M +H), 616

628(M +H), 629

628(M +H), 629

662(M +H), 664

668(M +H), 670

646(M +H), 648

702(M +H), 704

658(M +H), 660

672(M +H), 674

643(M +H), 645

766(M +H), 768

640(M +H), 642

668(M +H), 670

736(M +H), 738

716(M +H), 718

654(M +H), 656

680(M +H), 682

680(M +H), 682

640(M +H), 642

645(M +H), 647

846(M +H), 848

852(M +H), 854

R MS (APCI+)

619 (M + H)

673 (M + H)

593 (M + H)

565 (M + H)

659 (M + H)

R R²

640 (M + H) 642 694 (M + H) 696 614 (M + H) 616 680 (M + H) 682

619 (M + H) 673 (M + H) 593 (M + H) 658 (M + H)

566 (M + H) 620 (M + H) 540 (M + H) 606 (M + H)

631 (M + H) 685 (M + H) 605 (M + H) 671 (M + H)

R MS (APCI+)

600 (M + H), 602

658 (M + H), 660

586 (M + H), 588

642 (M + H), 644

668 (M + H), 670

668 (M + H), 670

662 (M + H), 664

628 (M + H), 630

646 (M + H), 648

736 (M + H), 738

655 (M + H), 656

640 (M + H), 642

600 (M + H), 602

646 (M + H), 648

614 (M + H), 616

628 (M + H), 630

672 (M + H), 674

R R²

666 (M + H) 652 (M + H) 586 (M + H)

669 (M + H) 655 (M + H) 590 (M + H)

644 (M + H) 630 (M + H) 564 (M + H)

646 (M + H) 632 (M + H) 566 (M + H)

R   R²

556 (M + H) 542 (M + H) 598 (M + H)

591 (M + H) 577 (M + H) 633 (M + H)

575 (M + H) 561 (M + H) 617 (M + H)

550 (M + H) 536 (M + H) 592 (M + H)

552 (M + H) 538 (M + H) 594 (M + H)

572 (M + H) 558 (M + H) 614 (M + H) R          R²       

        

624 (M + H) 624 (M + H) 602 (M + H)

659 (M + H) 659 (M + H) 637 (M + H)

643 (M + H) 643 (M + H) 621 (M + H)

618 (M + H) 618 (M + H) 596 (M + H)

620 (M + H) 620 (M + H) 598 (M + H)

640 (M + H) 640 (M + H) 618 (M + H) R    R²

  

  

692 (M + H) 570 (M + H) 584 (M + H)

727 (M + H) 605 (M + H) 619 (M + H)

711 (M + H) 589 (M + H) 603 (M + H)

686 (M + H) 564 (M + H) 578 (M + H)

688 (M + H) 566 (M + H) 580 (M + H)

708 (M + H) 586 (M + H) 600 (M + H)

R² MS (APCI+)

655 (M + H)

641 (M + H)

659 (M + H)

618 (M + H)

649 (M + H)

629 (M + H)

634 (M + H)

650 (M + H)

622 (M + H)

678 (M + H)

692 (M + H)

694 (M + H)

694 (M + H), 696

694 (M + H), 696

646 (M + H)

650 (M + H)

682 (M + H)

696 (M + H)

646 (M + H)

646 (M + H)

706 (M + H), 708

660 (M + H)

660 (M + H)

666 (M + H)

658 (M + H)

672 (M + H)

658 (M + H)

644 (M + H)

630 (M + H)

596 (M + H)

R³    R²

600 (M + H) 602 556 (M + H) 558 570 (M + H) 572 584 (M + H) 586

550 (M + H) 506 (M + H) 520 (M + H) 534 (M + H)

556 (M + H) 512 (M + H) 526 (M + H) 540 (M + H)

552 (M + H) 508 (M + H) 522 (M + H) 536 (M + H)

602 (M + H) 558 (M + H) 572 (M + H) 586 (M + H)

575 (M + H) 531 (M + H) 545 (M + H) 559 (M + H)

579 (M + H) 535 (M + H) 549 (M + H) 563 (M + H)

565 (M + H) 521 (M + H) 535 (M + H) 549 (M + H) R³      R²   

  

598 (M + H) 600 584 (M + H) 586 600 (M + H) 602 574 (M + H) 576

548 (M + H) 534 (M + H) 550 (M + H) 524 (M + H)

554 (M + H) 540 (M + H) 556 (M + H) 530 (M + H)

550 (M + H) 536 (M + H) 552 (M + H) 526 (M + H)

600 (M + H) 586 (M + H) 602 (M + H) 576 (M + H)

573 (M + H) 559 (M + H) 575 (M + H) 549 (M + H)

577 (M + H) 563 (M + H) 579 (M + H) 553 (M + H)

563 (M + H) 549 (M + H) 565 (M + H) 539 (M + H) R³       R²

624 (M + H) 626 606 (M + H) 608

574 (M + H) 556 (M + H)

580 (M + H) 562 (M + H)

576 (M + H) 558 (M + H)

626 (M + H) 608 (M + H)

599 (M + H) 581 (M + H)

603 (M + H) 585 (M + H)

589 (M + H) 570 (M + H)

R³       R²

   

638 (M + H) 640 576 (M + H) 578 613 (M + H) 615

588 (M + H) 526 (M + H) 563 (M + H)

594 (M + H) 532 (M + H) 569 (M + H)

590 (M + H) 528 (M + H) 565 (M + H)

640 (M + H) 578 (M + H) 615 (M + H)

617 (M + H) 555 (M + H) 592 (M + H)

603 (M + H) 541 (M + H) 578 (M + H) R³          R²

 

     

660 (M + H) 662 628 (M + H) 630 572 (M + H) 574

610 (M + H) 578 (M + H) 522 (M + H)

616 (M + H) 584 (M + H) 528 (M + H)

612 (M + H) 580 (M + H) 524 (M + H)

662 (M + H) 630 (M + H) 574 (M + H)

639 (M + H) 607 (M + H) 551 (M + H)

625 (M + H) 593 (M + H) 537 (M + H)

R³        R²

   

572 (M + H) 528 (M + H) 542 (M + H) 556 (M + H)

552 (M + H) 508 (M + H) 522 (M + H) 536 (M + H)

566 (M + H) 522 (M + H) 536 (M + H) 550 (M + H)

502 (M + H) 458 (M + H) 472 (M + H) 486 (M + H)

552 (M + H) 508 (M + H) 522 (M + H) 536 (M + H)

588 (M + H) 544 (M + H) 558 (M + H) 572 (M + H)

564 (M + H) 520 (M + H) 534 (M + H) 548 (M + H)

591 (M + H) 547 (M + H) 561 (M + H) 575 (M + H) R³          R²

    

  

    

570 (M + H) 546 (M + H) 596 (M + H) 548 (M + H)

550 (M + H) 526 (M + H) 576 (M + H) 528 (M + H)

564 (M + H) 540 (M + H) 590 (M + H) 542 (M + H)

500 (M + H) 476 (M + H) 526 (M + H) 478 (M + H)

550 (M + H) 526 (M + H) 576 (M + H) 528 (M + H)

586 (M + H) 562 (M + H) 612 (M + H) 564 (M + H)

562 (M + H) 538 (M + H) 588 (M + H) 540 (M + H)

589 (M + H) 565 (M + H) 615 (M + H) 567 (M + H) R³          R²

 

546 (M + H) 585 (M + H) 632 (M + H) 600 (M + H)

526 (M + H) 565 (M + H) 612 (M + H) 580 (M + H)

540 (M + H) 579 (M + H) 626 (M + H)    (M + H)

476 (M + H) 515 (M + H) 562 (M + H)    (M + H)

526 (M + H) 565 (M + H) 612 (M + H) 580 (M + H)

562 (M + H) 601 (M + H)    (M + H) 616 (M + H)

538 (M + H) 577 (M + H)    (M + H) 592 (M + H)

565 (M + H) 604 (M + H) 651 (M + H) 619 (M + H)

R³             R²       

     

 

   

605 (M + H) 607 550 (M + H) 552 625 (M + H) 627 639 (M + H) 641 618 (M +H) 620

555 (M + H) 500 (M + H) 575 (M + H) 589 (M + H) 568 (M + H)

561 (M + H) 506 (M + H) 581 (M + H) 595 (M + H) 574 (M + H)

557 (M + H) 502 (M + H) 577 (M + H) 591 (M + H) 570 (M + H)

584 (M + H) 529 (M + H) 604 (M + H) 618 (M + H) 597 (M + H)

570 (M + H) 515 (M + H) 590 (M + H) 604 (M + H) 583 (M + H)

577 (M + H) 522 (M + H) 597 (M + H) 611 (M + H) 590 (M + H)

557 (M + H) 502 (M + H) 577 (M + H) 591 (M + H) 570 (M + H) R³            R²

   

   

634 (M + H) 636 644 (M + H) 646 674 (M + H) 676

584 (M + H) 594 (M + H) 624 (M + H)

590 (M + H) 600 (M + H) 630 (M + H)

586 (M + H) 596 (M + H) 626 (M + H)

612 (M + H) 623 (M + H) 653 (M + H)

599 (M + H) 609 (M + H) 639 (M + H)

606 (M + H) 616 (M + H) 646 (M + H)

586 (M + H) 596 (M + H) 626 (M + H)

R³ R²

598 (M + H) 584 (M + H)

574 (M + H) 560 (M + H)

644 (M + H) 630 (M + H)

604 (M + H) 590 (M + H)

598 (M + H) 584 (M + H)

R³           R²

       

    

    

565 (M + H) 567 591 (M + H) 593 591 (M + H) 593 566 (M + H) 568

515 (M + H) 541 (M + H) 541 (M + H) 516 (M + H)

517 (M + H) 543 (M + H) 543 (M + H) 518 (M + H)

517 (M + H) 543 (M + H) 543 (M + H) 518 (M + H)

544 (M + H) 570 (M + H) 570 (M + H) 545 (M + H)

530 (M + H) 556 (M + H) 556 (M + H) 531 (M + H)

537 (M + H) 563 (M + H) 563 (M + H) 538 (M + H)

556 (M + H) 582 (M + H) 582 (M + H) 557 (M + H) R³         R²    

   

635 (M + H) 637 658 (M + H) 660 649 (M + H) 651

585 (M + H) 608 (M + H) 599 (M + H)

587 (M + H) 610 (M + H) 601 (M + H)

587 (M + H) 610 (M + H) 601 (M + H)

614 (M + H) 637 (M + H) 628 (M + H)

600 (M + H) 623 (M + H) 614 (M + H)

607 (M + H) 630 (M + H) 621 (M + H)

626 (M + H) 649 (M + H) 640 (M + H)

R³        R²

489 (M + H) 495 (M + H) 527 (M + H)

515 (M + H) 521 (M + H) 553 (M + H)

543 (M + H) 549 (M + H) 581 (M + H)

579 (M + H) 585 (M + H) 617 (M + H)

579 (M + H) 585 (M + H) 617 (M + H)

545 (M + H) 551 (M + H) 583 (M + H)

585 (M + H) 591 (M + H) 623 (M + H)

587 (M + H) 591 (M + H) 623 (M + H)

581 (M + H) 587 (M + H) 619 (M + H)

518 (M + H) 524 (M + H) 556 (M + H)

532 (M + H) 538 (M + H) 570 (M + H)

567 (M + H) 573 (M + H) 605 (M + H) R³           R²

  

549 (M + H) 487 (M + H) 502 (M + H)

575 (M + H) 513 (M + H) 528 (M + H)

603 (M + H) 541 (M + H) 556 (M + H)

639 (M + H) 577 (M + H) 592 (M + H)

639 (M + H) 577 (M + H) 592 (M + H)

605 (M + H) 543 (M + H) 558 (M + H)

645 (M + H) 583 (M + H) 598 (M + H)

647 (M + H) 585 (M + H) 600 (M + H)

641 (M + H) 579 (M + H) 594 (M + H)

578 (M + H) 516 (M + H) 531 (M + H)

592 (M + H) 530 (M + H) 545 (M + H)

627 (M + H) 565 (M + H) 580 (M + H)

R³        R²

600 (M + H)602 638 (M + H)640 606 (M + H)608

550 (M + H) 588 (M + H) 556 (M + H)

579 (M + H) 617 (M + H) 585 (M + H)

565 (M + H) 603 (M + H) 571 (M + H)

579 (M + H) 617 (M + H) 585 (M + H)

534 (M + H) 572 (M + H) 540 (M + H)

552 (M + H) 590 (M + H) 558 (M + H)

508 (M + H) 636 (M + H) 604 (M + H) R³           R²

  

660 (M + H)662 598 (M + H)600 613 (M + H)615

610 (M + H) 548 (M + H) 563 (M + H)

639 (M + H) 577 (M + H) 592 (M + H)

525 (M + H) 563 (M + H) 578 (M + H)

539 (M + H) 577 (M + H) 592 (M + H)

594 (M + H) 532 (M + H) 547 (M + H)

612 (M + H) 550 (M + H) 565 (M + H)

658 (M + H) 596 (M + H) 611 (M + H) R³         R²

     

649 (M + H)651 591 (M + H)593

599 (M + H) 541 (M + H)

628 (M + H) 570 (M + H)

614 (M + H) 556 (M + H)

628 (M + H) 570 (M + H)

583 (M + H) 525 (M + H)

601 (M + H) 543 (M + H)

647 (M + H) 589 (M + H)

R³        R²

600 (M + H)602 638 (M + H)640 606 (M + H)608

550 (M + H) 588 (M + H) 556 (M + H)

579 (M + H) 617 (M + H) 585 (M + H)

565 (M + H) 603 (M + H) 571 (M + H)

579 (M + H) 617 (M + H) 585 (M + H)

534 (M + H) 572 (M + H) 540 (M + H)

552 (M + H) 590 (M + H) 558 (M + H)

598 (M + H) 636 (M + H) 604 (M + H) R³           R²

  

660 (M + H662 598 (M + H)600 613 (M + H)615

610 (M + H) 548 (M + H) 563 (M + H)

639 (M + H) 577 (M + H) 592 (M + H)

625 (M + H) 563 (M + H) 578 (M + H)

639 (M + H) 577 (M + H) 592 (M + H)

594 (M + H) 532 (M + H) 547 (M + H)

612 (M + H) 550 (M + H) 565 (M + H)

658 (M + H) 596 (M + H) 611 (M + H) R³         R²

     

649 (M + H)651 591 (M + H)593

599 (M + H) 541 (M + H)

628 (M + H) 570 (M + H)

614 (M + H) 556 (M + H)

628 (M + H) 570 (M + H)

583 (M + H) 525 (M + H)

601 (M + H) 543 (M + H)

647 (M + H) 589 (M + H)

Hereinafter, the pharmaceutical activity of the compounds of the presentinvention is specifically illustrated, but is not limited thereto. Thegene manipulation procedures using Escherichia coli were carried outaccording to the methods described in the Molecular Cloning, 1989edition (Molecular Cloning, T. Maniatis et al.).

REFERENCE EXAMPLE 4

Cloning of Human Somatostatin Receptor Protein Subtype 5 (SSTR5) DNA

On the basis of a known nucleotide sequence of human SSTR5 cDNA[Biochem. Biophys. Res. Commun., 195: 844–852, 1993], DNA oligomers,S5-1 and S5-2 were synthesized. The sequence of S5-1 is5′-GGTCGACCACCATGGAGCCCCTGTTCCC-3′ (SEQ-ID NO:5) and the sequence ofS5-2 was 5′-CCGTCGACACTCTCACAGCTTGCTGG-3′ (SEQ ID NO:6). As a template,human chromosomal DNA (Catalog No. CL6550-1, Clontech) was used. 25 pmolof Each of the above DNA oligomers was added to 0.5 ng of the templateDNA and subjected to polymerase chain reaction with 2.5 U of Pfu DNApolymerase (Stratagene). The composition of the reaction mixturefollowed instructions attached to the Pfu DNA polymerase. In thereaction, 35 cycles each consisting of heating at 94° C. for 1 minute,at 66° C. for 1 minute and at 75° C. for 2 minutes were carried out.Electrophoresis of the reaction mixture on 1% agarose gel indicated thata DNA fragment of intended size (about 1.1 kb) was specificallyamplified. This DNA fragment was recovered in a usual manner from theagarose gel, then ligated to pUC118 previously cleaved at its Hinc IIsite, and transformed into competent cells, Escherichia coli JM109. Atransformant having a plasmid containing the DNA fragment was selected,and the nucleotide sequence of the insert DNA fragment, confirmed by anautomatic nucleotide sequencer ALF DNA sequencer (Pharmacia) using afluorescent coloring matter, indicated that an amino acid sequencededuced from the nucleotide sequence agreed completely with a sequencedescribed in the literature supra.

REFERENCE EXAMPLE 5

Construction of Human Somatostatin Receptor Protein Subtype 5 (SSTR5)DNA Expression Plasmid

As an expression vector in CHO (Chinese hamster ovary) cells, pAKKO-111was used. pAKKO-111 was constructed in the following manner. pTB1417described in JP 5-076385 A was treated with Hind III and Cla I to give a1.4 kb DNA fragment containing an SR• promoter and a polyA-added signal.Separately, pTB348 (Biochem. Biophys. Res. Commun., 128: 256–264, 1985)was treated with Cla I and Sal I, to give a 4.5 kb DNA fragmentcontaining a dihydrofolate reductase (DHFR) gene. These DNA fragmentswere blunt-ended by treatment with T4 polymerase and then ligated toeach other by treatment with T4 ligase, to construct pAKKO-111 plasmid.5 •g of Plasmid having the human SSTR5 DNA fragment obtained inReference Example 4 was digested with a restriction enzyme Sal I andthen subjected to 1% agarose gel electrophoresis, and a 1.1 kb DNAfragment encoding human SSTR5 was recovered. Then, 1 •g of theexpression vector pAKKO-111 (5.5 kb) was digested with Sal I, to preparea cloning site for the inserting human SSTR5 DNA fragment into it. Thisexpression vector fragment and the 1.1 kb DNA fragment were ligated toeach other with T4 DNA ligase, and the reaction mixture was introducedinto E. coli JM109 by calcium chloride method, and an expression plasmidpA-1-11-SSTR5 having the human SSTR5 DNA fragment inserted in the normaldirection into the promoter was obtained from the resultanttransformant.

REFERENCE EXAMPLE 6

Introduction of Human Somatostatin Receptor Protein Subtype 5 (SSTR5)DNA into CHO (dhfr⁻) Cells and Expression of the DNA

1×10⁶ CHO (dhfr⁻) cells were cultured for 24 hours in HAM F12 mediumcontaining 10% fetal bovine serum in a Petri dish of 8 cm in diameter,and 10 •g of the human SSTR5 cDNA expression plasmid pA-1-11-SSTR5obtained in Reference Example 5 was introduced into the cells byphosphate calcium method. 24 Hours after this introduction, the mediumwas exchanged with a DMEM medium containing 10% dialyzed fetal bovineserum, and colony-forming cells in the medium (that is, DHFR⁺ cells)were selected. A single cell obtained by limiting dilution from theselected cells was cloned and measured for the ability to express asomatostatin receptor protein in the following manner. The human SSTR5cDNA-expressing cell strain was diluted with a measurement buffer [50 mMTris-HCl buffer (pH 7.5) containing 1 mM EDTA, 5 mM magnesium chloride,0.1% BSA, 0.2 mg/ml bacitracin, 10 •g/ml leupeptin, 1 •g/ml pepstatin,200 units/ml aprotinin], to prepare a cell suspension containing 2×10⁴cells/200 •l. In to a tube, 200 •l of the cell suspension was pipetted,and 2 •l of 5 nM [¹²⁵I]-somatostatin (2000 Ci/mmol, Amersham) was addedthereto and incubated at 25° C. for 60 minutes. To measure nonspecificbinding (NSB), a tube containing 2 •l (10⁻⁴ M) of somatostatin-14 wasalso incubated. 1.5 ml of Washing buffer [50 mM Tris-HCl buffer (pH 7.5)containing 1 mM EDTA, 5 mM magnesium chloride] was added to the samplewhich was then filtered with a GF/F glass fiber filter paper (Whatman)and then washed with the same buffer. [¹²⁵I] of the filter paper wasmeasured by a •-counter. SSTR5-32-4 was selected as a cell strain havinga higher somatostatin binding activity.

EXPERIMENTAL EXAMPLE 5

Preparation of CHO Cell Membrane Fraction Containing Human SomatostatinReceptor Protein Subtype 5 (SSTR5)

The human somatostatin receptor protein subtype 5-expressing CHO cellstrain, SSTR5-32-4 (10⁹ cells), were suspended in phosphate-bufferedphysiological saline containing 5 mM EDTA (PBS-EDTA) and centrifuged. Tothe cell pellet, 10 ml of homogenate buffer (10 mM NaHCO₃, 5 mM EDTA, pH7.5) was added, which was then homogenated with a polytron homogenizer.The homogenate was centrifuged at 400×g for 15 minutes, and theresultant supernatant was further centrifuged at 100,000×g for 1 hour,to give precipitates of the membrane fraction. The precipitates weresuspended in 2ml of assay buffer [25 mM Tris-HCl buffer (pH 7.5)containing 1 mM EDTA, 0.1% BSA (bovine serum albumin), 0.25 mM PMSF, 1•g/ml pepstatin, 20 •g/ml leupeptin, 10 •g/ml phosphoramidon) andcentrifuged at 100,000×g for 1 hour. The membrane fraction recovered asprecipitates was suspended again in 20 ml of assay buffer, pipetted,stored at −80° C. and thawed just before use.

EXPERIMENTAL EXAMPLE 6

Measurement of the Degree of Inhibition of Binding to[¹²⁵I]-Somatostatin

The SSTR5-expressing CHO cell membrane fraction prepared in Example 5was diluted with the assay buffer to prepare a solution at aconcentration of 3 •g/ml and pipetted into tubes (173 •l/tube). Two •lof compound dissolved in DMSO and 25 •l of 200 pM [¹²⁵I]-somatostatin(Amersham) were added simultaneously thereto. To measure the maximumbinding, a reaction mixture containing 2 •l of DMSO and 25 •l of 200 pM[¹²⁵I]-somatostatin was prepared. To measure nonspecific binding, areaction mixture containing 2 •l of 100 •M somatostatin in DMSO and 25•l of 200 pM [¹²⁵I]-somatostatin was also simultaneously prepared. Eachreaction mixture was reacted at 25° C. for 60 minutes and then filteredunder suction with a polyethylene imine-treated Whatman glass filter(GF/B). After filtration, the radioactivity of [¹²⁵I]-somatostatinremaining on the glass filer was measured with a • counter.

The degree of inhibition of binding (%) by each test substance wasdetermined according to the following equation:The degree of inhibition of binding (%)=(radioactivity when the compoundwas added−radioactivity when DMSO solution was added)/(radioactivitywhen somatostatin was added−radioactivity when DMSO solution wasadded)×100.

While the concentration of the test substance was changed, theconcentration of the test substance at which 50% binding was inhibited(IC₅₀ value) was calculated from Hill plots.

The results are shown below:

Test Compound IC₅₀ Example 325 6 nM Example 328 3 nM

INDUSTRIAL APPLICABILITY

Since the compounds [compounds of the formula (I) or salts thereof]having an antagonistic activity on GPR14 of the present invention have astrong antagonistic activity on GPR14, they can be advantageously usedas various vasoactive drugs (preferably vasoconstriction inhibitor) andfor treating various diseases (preferably treating ischemic myocardialinfarction, congestive heart failure and the like).

Further since the compounds of the formula (I) or salts thereof of thepresent invention have an excellent somatostatin receptor-bindingactivity. Accordingly, compound (I) is useful for treating abnormalities(e.g., diseases accompanied by excessive promotion or suppression) inthe intracellular information transmission system of mammals, diseasesaccompanied by abnormalities in regulation of cell proliferation, anddiseases accompanied by abnormalities in production and/or secretion ofhormones, growth factors, physiologically active substances, etc.

1. A compound represented by the formula (I):

wherein R¹ is (1) hydrogen atom; (2) C₁₋₁₀alkyl which may have 1 to 3substituents selected from (1′) halogen atom, (2′) nitro, (3′) cyano,(4′) oxo, (5′) hydroxyl group, (6′) thiol, (7′) C₁₋₄alkylthio, (8′)amino group, (9′) mono-C₁₋₄alkylamino, (10′) di-C₁₋₄alkylamino, (11′) 5-to 6-membered cyclic amino selected from tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole,2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinyl, (12′) phenyl-C₁₋₄alkyl,(13′) C₃₋₇cycloalkyl, (14′) carboxyl, (15′) C₁₋₄alkoxy-carbonyl, (16′)C₇₋₁₀aralkyloxy-carbonyl, (17′) carbamoyl, (18′)mono-C₁₋₄alkylcarbamoyl, (19′) di-C₁₋₄alkylcarbamoyl, (20′) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (21′)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(22′) C₁₋₄alkylenedioxy, (23′) formyl, (24′) C₂₋₄alkanoyl, (25′)C₁₋₄alkylsulfonyl, (26′) C₁₋₄alkylsulfinyl, (27′) sulfamoyl, (28′)mono-C₁₋₄alkylsulfamoyl, (29′) di-C₁₋₄alkylsulfamoyl, (30′) C₆₋₁₄aryl(which may be substituted with a substituent(s) selected from (1″)halogen, (2″) nitro, (3″) cyano, (4″) hydroxyl group, (5″) thiol, (6″)C₁₋₄alkylthio, (7″) amino, (8″) mono-C₁₋₄alkylamino, (9″)di-C₁₋₄alkylamino, (10″) 5- to 6-membered cyclic amino selected fromtetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole and imidazole, (11″) phenyl-C₁₋₄alkyl, (12″) C₃₋₇cycloalkyl,(13″) carboxyl group, (14″) C₁₋₄alkoxy-carbonyl, (15″)C₇₋₁₀aralkyloxy-carbonyl, (16″) carbamoyl, (17″)mono-C₁₋₄alkyl-carbamoyl, (18″) di-C₁₋₄alkyl-carbamoyl, (19″) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (20″)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(21″) C₁₋₄alkylenedioxy, (22″) formyl, (23″) C₂₋₄alkanoyl, (24″)C₁₋₄alkylsulfonyl, (25″) C₁₋₄alkylsulfinyl, (26″) sulfamoyl, (27″)mono-C₁₋₄alkylsulfamoyl, (28″) di-C₁₋₄alkylsulfamoyl and (29″) 5- to6-membered aromatic monocyclic heterocyclic group), and (31′) 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom(said heterocyclic group may have 1 to 3 substituents selected from (1″)halogen, (2″) nitro, (3″) cyano, (4″) oxo, (5″) hydroxyl group, (6″)thiol, (7″) C₁₋₄alkylthio, (8″) amino, (9″) mono-C₁₋₄alkylamino, (10″)di-C₁₋₄alkylamino, (11″) 5- to 6-membered cyclic amino selected fromtetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole and imidazole, (12″) phenyl-C₁₋₄alkyl, (13″) C₃₋₇cycloalkyl,(14″) carboxyl, (15″) C₁₋₄alkoxy-carbonyl, (16″)C₇₋₁₀aralkyloxy-carbonyl, (17″) carbamoyl, (18″)mono-C₁₋₄alkyl-carbamoyl, (19″) di-C₁₋₄alkyl-carbamoyl, (20″) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (21″)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(22″) C₁₋₄alkylenedioxy, (23″) formyl, (24″) C₂₋₄alkanoyl, (25″)C₁₋₄alkylsulfonyl, and (26″) C₁₋₄alkylsulfinyl) (hereinafter referred toas substituent group A); (3) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group A; (4) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupA; (5) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group A; (6) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group A; (7) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group A; (8)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group A; (9) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group A; (10)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (11) a group represented by the formula—X′″—G—(CH₂)_(n)—J wherein X′″ represents C₁₋₄alkylene orC₂₋₄alkenylene, G is a bond, —O—, —S—, —CO—NH— or —NH—CO—, n is aninteger of 0 to 3, J represents (a) C₆₋₁₄aryl (which may have 1 to 3substituents selected from (1″) halogen, (2″) nitro, (3″) cyano, (4″)hydroxyl group, (5″) thiol, (6″) C₁₋₄alkylthio, (7″) amino, (8″)mono-C₁₋₄alkylamino, (9″) di-C₁₋₄alkylamino, (10″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, 2-oxo-1-pyrrolidinyl and2-oxo-1-piperidinyl, (11″) phenyl-C₁₋₄alkyl, (12″) C₃₋₇cycloalkyl, (13″)carboxyl, (14″) C₁₋₄alkoxy-carbonyl, (15″) C₇₋₁₀aralkyloxy-carbonyl,(16″) carbamoyl, (17″) mono-C₁₋₄alkyl-carbamoyl, (18″)di-C₁₋₄alkyl-carbamoyl, (19″) C₁₋₄alkyl which may be substituted with ahalogen atom or C₁₋₄alkoxy, (20″) C₁₋₄alkoxy which may be substitutedwith a halogen atom or C₁₋₄alkoxy, (21″) C₁₋₄alkylenedioxy, (22″)formyl, (23″) C₂₋₄alkanoyl, (24″) C₁₋₄alkylsulfonyl, (25″)C₁₋₄alkylsulfinyl, (26″) sulfamoyl, (27″) mono-C₁₋₄alkylsulfamoyl, (28″)di-C₁₋₄alkylsulfamoyl, (29″) C₆₋₁₄aryl (which may be substituted with asubstituent(s) selected from (1′″) halogen, (2′″) nitro, (3′″) cyano,(4′″) hydroxyl group, (5′″) thiol, (6′″) C₁₋₄alkylthio, (7′″) amino,(8′″) mono-C₁₋₄alkylamino, (9′″) di-C₁₋₄alkylamino, (10′″) 5- to6-membered cyclic amino selected from tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole and imidazole, (11′″)phenyl-C₁₋₄alkyl, (12′″) C₃₋₇cycloalkyl, (13′″) carboxyl group, (14′″)C₁₋₄alkoxy-carbonyl, (15′″) C₇₋₁₀aralkyloxy-carbonyl, (16′″) carbamoyl,(17′′) mono-C₁₋₄alkyl-carbamoyl, (18′″) di-C₁₋₄alkyl-carbamoyl, (19′″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(20′″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (21′″) C₁₋₄alkylenedioxy, (22′″) formyl, (23′″)C₂₋₄alkanoyl, (24′″) C₁₋₄alkylsulfonyl, (25′″) C₁₋₄alkylsulfinyl, (26′″)sulfamoyl, (27′″) mono-C₁₋₄alkylsulfamoyl, (28′″) di-C₁₋₄alkylsulfamoyl,and (29′″) 5- to 6-membered aromatic monocyclic heterocyclic group), and(30″) 5- to 8-membered aromatic heterocyclic group or saturated orunsaturated non-aromatic heterocyclic group containing at least one of 1to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom (said heterocyclic group may have 1 to 3 substituentsselected from (1′″) halogen, (2′″) nitro, (3′″) cyano, (4′″) oxo, (5′″)hydroxyl group, (6′″) thiol, (7′″) C₁₋₄alkylthio, (8′″) amino, (9′″)mono-C₁₋₄alkylamino, (10′″) di-C₁₋₄alkylamino, (11′″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (12′″)phenyl-C₁₋₄alkyl, (13′″) C₃₋₇cycloalkyl, (14′″) carboxyl, (15′″)C₁₋₄alkoxy-carbonyl, (16′″) C₇₋₁₀aralkyloxy-carbonyl, (17′″) carbamoyl,(18′″) mono-C₁₋₄alkyl-carbamoyl, (19′″) di-C₁₋₄alkyl-carbamoyl, (20′″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(21′″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (22′″) C₁₋₄alkylenedioxy, (23′″) formyl, (24′″)C₂₋₄alkanoyl, (25′″) C₁₋₄alkylsulfonyl and (26′″) C₁₋₄alkylsulfinyl)(hereinafter referred to as substituent group B), or (b) a 5- to8-membered aromatic heterocyclic group containing at least one of 1 to 3kinds of heteroatoms selected from oxygen atom, sulfur atom and nitrogenatom (said aromatic heterocyclic group optionally having 1 to 3substituents selected from the substituent group B); or (12) a grouprepresented by the formula —X″″—L—(CH₂)_(n)—M wherein X″″ represents abond or a C₁₋₄alkylene group which may have 1 to 3 substituents selectedfrom the substituent group A, L represents (a) a bond, (b) C₆₋₁₀arylwhich may have 1 to 3 substituents selected from the substituent groupB, (c) a 5- to 8-membered aromatic heterocyclic group containing atleast one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom (said aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup B), (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—, n is an integerof 0 to 3, and M represents amino group, guanidino group, sulfamoylgroup, carbamoyl group or hydroxyl group, X represents: (1)—(CH₂)_(f1)—, wherein f1 represents an integer of 1 to 12, (2)—(CH₂)_(g1)—X¹—(CH₂)_(g2)—, wherein g1 and g2 are the same or different,and represent an integer of 0 to 11, provided that the sum of g1 and g2is 0 to 11, and X¹ represents NH, O, S, SO or SO₂, or (3)—(CH₂)_(h1)—X¹—(CH₂)_(h2)—X²—(CH₂)_(h3)— wherein h1, h2 and h3 are thesame or different, and represent an integer of 0 to 10, provided thatthe sum of h1, h2 and h3 is 0 to 10, and X¹ and X² each represents NH,O, S, SO or SO₂ provided that when h2 is 0, X¹ _(and/or X) ² preferablyrepresent NH, A represents (1) amino which may have 1 to 2 substituentsselected from (a) C₁₋₁₀alkyl which may have 1 to 3 substituents selectedfrom (1″) halogen, (2″) nitro, (3″) cyano, (4″) oxo, (5″) hydroxylgroup, (6″) thiol, (7″) C₁₋₄alkylthio, (8″) amino, (9″)mono-C₁₋₄alkylamino, (10″) di-C₁₋₄alkylamino, (11″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (12″)phenyl-C₁₋₄alkyl, (13″) C₃₋₇cycloalkyl, (14″) carboxyl, (15″)C₁₋₄alkoxy-carbonyl, (16″) C₇₋₁₀aralkyloxy-carbonyl, (17″) carbamoyl,(18″) mono-C₁₋₄alkyl-carbamoyl, (19″) di-C₁₋₄alkyl-carbamoyl, (20″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(21″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (22″) C₁₋₄alkylenedioxy, (23″) formyl, (24″) C₂₋₄alkanoyl,(25″) C₁₋₄alkylsulfonyl and (26″) C₁₋₄alkylsulfinyl (hereinafterreferred to as substituent group C), (b) C₃₋₈cycloalkyl which may have 1to 3 substituents selected from the substituent group C, (c)C₂₋₁₀alkenyl which may have 1 to 3 substituents selected from thesubstituent group C, (d) C₃₋₈cycloalkenyl which may have 1 to 3substituents selected from the substituent group C, (e) C₂₋₁₀alkynylwhich may have 1 to 3 substituents selected from the substituent groupC, (f) C₆₋₁₄aryl which may have 1 to 3 substituents selected from thesubstituent group C, (g) C₆₋₁₄ aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group C, (h)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group C, (i) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group C, (j) a 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom,which may have 1 to 3 substituents selected from the substituent groupC, (k) acyl selected from formyl, C₁₋₁₀alkyl-carbonyl,C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup C), and (l) acyl groups wherein a 5- to 8-membered aromaticheterocyclic group or saturated or unsaturated non-aromatic heterocyclicgroup containing a least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom has been bound tocarbonyl or sulfonyl (said acyl optionally having 1 to 3 substituentsselected from the substituent group C); or (2) 5- or 6-membered cyclicamino which may have 1 to 3 substituents selected from (a) halogen, (b)nitro, (c) cyano, (d) hydroxyl group, (e) thiol, (f) amino, (g)carboxyl, (h) optionally halogenated C₁₋₄alkyl, (i) optionallyhalogenated C₁₋₄alkoxy, (j) formyl, (k) C₂₋₄alkanoyl and (l)C₁₋₄alkylsulfonyl; or (3) a heterocyclic group formed by removing onehydrogen atom from a 5- to 8-membered aromatic monocyclic heterocyclicring or saturated or unsaturated non-aromatic monocyclic heterocyclicring containing one nitrogen atom and one to three kinds of 1 to 4heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom orby removing one hydrogen atom from a ring wherein 2 or 3 the same ordifferent rings selected from the above monocyclic rings have been fused(said heterocyclic group optionally having 1 to 3 substituents selectedfrom the substituent group C), R² represents (1) C₁₋₁₀alkyl which mayhave 1 to 3 substituents selected from the substituent group A; (2)C₃₋₈cycloalkyl which may have 1 to 3 substituents selected from thesubstituent group A; (3) C₂₋₁₀alkenyl which may have 1 to 3 substituentsselected from the substituent group A; (4) C₃₋₈cycloalkenyl which mayhave 1 to 3 substituents selected from the substituent group A; (5)C₂₋₁₀alkynyl which may have 1 to 3 substituents selected from thesubstituent group A; (6) C₆₋₁₄aryl which may have 1 to 3 substituentsselected from the substituent group A; (7) C₆₋₁₄aryl-C₁₋₆alkyl which mayhave 1 to 3 substituents selected from the substituent group A; (8)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (9) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group A; (10) a grouprepresented by the formula —X′″—G—(CH₂)_(n)—J, wherein X′″ representsC₁₋₄alkylene or C₂₋₄alkenylene, G represents a bond, —O—, —S—, —CO—NH—or —NH—CO—, n is an integer of 0 to 3, and J represents (a) C₆₋₁₄aryl(which may have 1 to 3 substituents selected from the substituent groupB) or (b) a 5- to 8-membered aromatic heterocyclic group which may haveat least one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom (said aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup B); (11) a group represented by the formula —X″″—L—(CH₂)_(n)—M,wherein X″″ represents a bond or C₁₋₄alkylene which may have 1 to 3substituents selected from the substituent group A, and L represents (a)a bond, (b) C₆₋₁₀aryl which may have 1 to 3 substituents selected fromthe substituent group B, (c) a 5- to 8-membered aromatic heterocyclicgroup containing at least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom (said aromaticheterocyclic group optionally having 1 to 3 substituents selected fromthe substituent group B), (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—,n is an integer of 0 to 3, M represents an amino group, guanidino group,sulfamoyl group, carbamoyl group or hydroxyl group; or (12) amino whichmay have 1 to 2 substituents selected from (a) C₁₋₁₀alkyl which may have1 to 3 substituents selected from the substituent group C, (b)C₃₋₈cycloalkyl which may have 1 to 3 substituents selected from thesubstituent group C, (c) C₂₋₁₀alkenyl which may have 1 to 3 substituentsselected from the substituent group C, (d) C₃₋₈cycloalkenyl which mayhave 1 to 3 substituents selected from the substituent group C, (e)C₂₋₁₀alkynyl which may have 1 to 3 substituents selected from thesubstituent group C, (f) C₆₋₁₄aryl which may have 1 to 3 substituentsselected from the substituent group C, (g) C₆₋₁₄aryl-C₁₋₆alkyl which mayhave 1 to 3 substituents selected from the substituent group C, (h)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group C, (i) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group C, (j) a 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom,which may have 1 to 3 substituents selected from the substituent groupC, (k) acyl selected from formyl, C₁₋₁₀alkyl-carbonyl,C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup C), and (l) acyl groups wherein a 5- to 8-membered aromaticheterocyclic group or saturated or unsaturated non-aromatic heterocyclicgroup containing a least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom has been bound to acarbonyl or sulfonyl group (said acyl optionally having 1 to 3substituents selected from the substituent group C), R³ represents (1)C₁₋₁₀alkyl which may have 1 to 3 substituents selected the substituentgroup A; (2) C₃₋₈cycloalkyl which may have 1 to 3 substituents selectedfrom the substituent group A; (3) C₂₋₁₀alkenyl which may have 1 to 3substituents selected from the substituent group A; (4) C₃₋₈cycloalkenylwhich may have 1 to 3 substituents selected from the substituent groupA; (5) C₂₋₁₀alkynyl which may have 1 to 3 substituents selected from thesubstituent group A; (6) C₆₋₁₄aryl which may have 1 to 3 substituentsselected from the substituent group A; (7) C₆₋₁₄aryl-C₁₋₆alkyl which mayhave 1 to 3 substituents selected from the substituent group A; (8)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (9) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group A; (10) a grouprepresented by the formula —X′″—G—(CH₂)_(n)—J, wherein X′″ representsC₁₋₄alkylene or C₂₋₄alkenylene, G represents a bond, —O—, —S—, —CO—NH—or —NH—CO—, n is an integer of 0 to 3, and J represents (a) a C₆₋₁₄arylgroup (which may have 1 to 3 substituents selected from the substituentgroup B) or (b) a 5- to 8-membered aromatic heterocyclic group which mayhave at least one of 1 to 3 kinds of heteroatoms selected from oxygenatom, sulfur atom and nitrogen atom (said aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup B); or (11) a group represented by the formula —X″″—L—(CH₂)_(n)—M,wherein X″″ represents a bond or C₁₋₄alkylene which may have 1 to 3substituents selected from the substituent group A, and L represents (a)a bond, (b) C₆₋₁₀aryl (which may have 1 to 3 substituents selected fromthe substituent group B), or (c) a 5- to 8-membered aromaticheterocyclic group containing at least one of 1 to 3 kinds ofheteroatoms selected from oxygen atom, sulfur atom and nitrogen atom(said aromatic heterocyclic group optionally having 1 to 3 substituentsselected from the substituent group B), (d) —O—, (e) —S—, (f) —CO—NH— or(g) —NH—CO—, n is an integer of 0 to 3, M represents amino group,guanidino group, sulfamoyl group, carbamoyl group or hydroxyl group; andrings B and C each represent a benzene ring which may further have 1 to4 substituents selected from (1) C₁₋₁₀alkyl which may have 1 to 3substituents selected from the substituent group A; (2) C₃₋₈cycloalkylwhich may have 1 to 3 substituents selected from the substituent groupA; (3) C₂₋₁₀alkenyl which may have 1 to 3 substituents selected from thesubstituent group A; (4) C₃₋₈cycloalkenyl which may have 1 to 3substituents selected from the substituent group A; (5) C₂₋₁₀alkynylwhich may have 1 to 3 substituents selected from the substituent groupA; (6) C₆₋₁₄aryl which may have 1 to 3 substituents selected from thesubstituent group A; (7) C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group A; (8)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (9) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group A; (10) aheterocyclic group formed by removing one hydrogen atom from a 5- to8-membered aromatic monocyclic heterocyclic ring or saturated orunsaturated non-aromatic monocyclic heterocyclic ring containing atleast 1 of one to three kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom or by removing one hydrogen atom from aring wherein 2 or 3 of the same or different rings selected from theabove monocyclic rings and 5- to 8-membered cyclic hydrocarbons havebeen fused (said heterocyclic group optionally having 1 to 3substituents selected from the substituent group A); (11) a halogenatom; (12) amino which may have 1 to 2 substituents selected from (a)C₁₋₁₀alkyl which may have 1 to 3 substituents selected from thesubstituent group C, (b) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group C, (c) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupC, (d) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group C, (e) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group C, (f) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group C, (g)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group C, (h) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group C, (i)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group C, (j) a 5- to 8-membered aromatic heterocyclicgroup or saturated or unsaturated non-aromatic heterocyclic groupcontaining at least one of 1 to 3 kinds of heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom, which may have 1 to 3substituents selected from the substituent group C, (k) acyl selectedfrom formyl, C₁₋₁₀alkyl-carbonyl, C₃₋₈cycloalkyl-carbonyl,C₂₋₁₀alkenyl-carbonyl, C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl,C₆₋₁₄aryl-carbonyl, C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,C₁₋₁₀alkylsulfonyl, C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl,C₃₋₈cycloalkenylsulfonyl, C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl,C₆₋₁₄aryl-C₁₋₆alkylsulfonyl, di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl ortri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (said acyl optionally having 1 to 3substituents selected from the substituent group C), and (l) acyl groupswherein a 5- to 8-membered aromatic heterocyclic group or saturated orunsaturated non-aromatic heterocyclic group containing at least one of 1to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom has been bound to carbonyl or sulfonyl (said acyloptionally having 1 to 3 substituents selected from the substituentgroup C); (13) 5- or 6-membered cyclic amino which may have 1 to 3substituents selected from (a) halogen, (b) nitro, (c) cyano, (d)hydroxyl group, (e) thiol, (f) amino, (g) carboxyl, (h) optionallyhalogenated C₁₋₄alkyl, (i) optionally halogenated C₁₋₄alkoxy, (j)formyl, (k) C₂₋₄alkanoyl and (l) C₁₋₄alkylsulfonyl; (14) a grouprepresented by the formula: R⁶—Y— (wherein Y is O, S, S(O) or S(O)₂, andR⁶ is (i) C₁₋₁₀alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (ii) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group A; (iii) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupA; (iv) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selectedfrom the substituent group A; (v) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group A; (vi) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group A;(vii) C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selectedfrom the substituent group A; (viii) di-C₆₋₁₄aryl-C₁₋₆alkyl which mayhave 1 to 3 substituents selected from the substituent group A; (ix)tri-C₆₋₁₄ aryl-C₁₋₆alkyl which may have 1 to 3 substituents selectedfrom the substituent group A; or (x) a heterocyclic group formed byremoving one hydrogen atom from a 5- to 8-membered aromatic monocyclicheterocyclic ring or saturated or unsaturated non-aromatic monocyclicheterocyclic ring containing at least 1 of one to three kinds ofheteroatoms selected from oxygen atom, sulfur atom and nitrogen atom orby removing one hydrogen atom from a ring wherein 2 or 3 of the same ordifferent rings selected from the above monocyclic rings and 5- to8-membered cyclic hydrocarbons have been fused (said heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup A)); (15) cyano group; (16) acyl selected from formyl,C₁₋₁₀alkyl-carbonyl, C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup C); (17) acyl groups wherein a 5- to 8-membered aromaticheterocyclic group or saturated or unsaturated non-aromatic heterocyclicgroup containing at least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom has been bound tocarbonyl or sulfonyl (said acyl optionally having 1 to 3 substituentsselected from the substituent group C); (18) carboxyl; and (19)carbamoyl which may have 1 to 2 substituents selected from (a)C₁₋₁₀alkyl which may have 1 to 3 substituents selected from thesubstituent group C, (b) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group C, (c) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupC, (d) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group C, (e) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group C, (f) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group C, (g)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group C, (h) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group C, (i)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group C and (j) a 5- to 8-membered aromatic heterocyclicgroup or saturated or unsaturated non-aromatic heterocyclic groupcontaining at least one of 1 to 3 kinds of heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom, which may have 1 to 3substituents selected from the substituent group C; or a salt thereof,provided that (1) a compound represented by the formula:

wherein each symbol is as defined above and (2)4′-[[(methoxyacetyl)methylamino]methyl]-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-[1,1′-biphenyl]-4-carboxamideare excluded.
 2. A compound represented by formula (I):

wherein R¹ is (1) hydrogen atom; (2) C₁₋₁₀alkyl which may have 1 to 3substituents selected from (1′) halogen atom, (2′) nitro, (3′) cyano,(4′) oxo, (5′) hydroxyl group, (6′) thiol, (7′) C₁₋₄alkylthio, (8′)amino group, (9′) mono-C₁₋₄alkylamino, (10′) di-C₁₋₄alkylamino, (11′) 5-to 6-membered cyclic amino selected from tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole,2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinyl, (12′) phenyl-C₁₋₄alkyl,(13′) C₃₋₇cycloalkyl, (14′) carboxyl, (15′) C₁₋₄alkoxy-carbonyl, (16′)C₇₋₁₀aralkyloxy-carbonyl, (17′) carbamoyl, (18′)mono-C₁₋₄alkylcarbamoyl, (19′) di-C₁₋₄alkylcarbamoyl, (20′) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (21′)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(22′) C₁₋₄alkylenedioxy, (23′) formyl, (24′) C₂₋₄alkanoyl, (25′)C₁₋₄alkylsulfonyl, (26′) C₁₋₄alkylsulfinyl, (27′) sulfamoyl, (28′)mono-C₁₋₄alkylsulfamoyl, (29′) di-C₁₋₄alkylsulfamoyl, (30′) C₆₋₁₄aryl(which may be substituted with a substituent(s) selected from (1″)halogen, (2″) nitro, (3″) cyano, (4″) hydroxyl group, (5″) thiol, (6″)C₁₋₄alkylthio, (7″) amino, (8″) mono-C₁₋₄alkylamino, (9″)di-C₁₋₄alkylamino, (10″) 5- to 6-membered cyclic amino selected fromtetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole and imidazole, (11″) phenyl-C₁₋₄alkyl, (12″) C₃₋₇cycloalkyl,(13″) carboxyl group, (14″) C₁₋₄alkoxy-carbonyl, (15″)C₇₋₁₀aralkyloxy-carbonyl, (16″) carbamoyl, (17″)mono-C₁₋₄alkyl-carbamoyl, (18″) di-C₁₋₄alkyl-carbamoyl, (19″) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (20″)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(21″) C₁₋₄alkylenedioxy, (22″) formyl, (23″) C₂₋₄alkanoyl, (24″)C₁₋₄alkylsulfonyl, (25″) C₁₋₄alkylsulfinyl, (26″) sulfamoyl, (27″)mono-C₁₋₄alkylsulfamoyl, (28″) di-C₁₋₄alkylsulfamoyl, and (29″) 5- to6-membered aromatic monocyclic heterocyclic group), or (31′) 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom(said heterocyclic group may have 1 to 3 substituents selected from (1″)halogen, (2″) nitro, (3″) cyano, (4″) oxo, (5″) hydroxyl group, (6″)thiol, (7″) C₁₋₄alkylthio, (8″) amino, (9″) mono-C₁₋₄alkylamino, (10″)di-C₁₋₄alkylamino, (11″) 5- to 6-membered cyclic amino selected fromtetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole and imidazole, (12″) phenyl-C₁₋₄alkyl, (13″) C₃₋₇cycloalkyl,(14″) carboxyl, (15″) C₁₋₄alkoxy-carbonyl, (16″)C₇₋₁₀aralkyloxy-carbonyl, (17″) carbamoyl, (18″)mono-C₁₋₄alkyl-carbamoyl, (19″) di-C₁₋₄alkyl-carbamoyl, (20″) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (21″)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(22″) C₁₋₄alkylenedioxy, (23″) formyl, (24″) C₂₋₄alkanoyl, (25″)C₁₋₄alkylsulfonyl and (26″) C₁₋₄alkylsulfinyl) (hereinafter referred toas substituent group D); (3) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group D; (4) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupD; (5) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group D; (6) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group D; (7) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group D; (8)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group D; (9) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group D; (10)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group D; (11) a group represented by the formula—X′″—G—(CH₂)_(n)—J, wherein X′″ represents C₁₋₄alkylene orC₂₋₄alkenylene, G is a bond, —O—, —S—, —CO—NH— or —NH—CO—, n is aninteger of 0 to 3, J represents (a) C₆₋₁₄aryl (which may have 1 to 3substituents selected from (1″) halogen, (2″) nitro, (3″) cyano, (4″)hydroxyl group, (5″) thiol, (6″) C₁₋₄alkylthio, (7″) amino, (8″)mono-C₁₋₄alkylamino, (9″) di-C₁₋₄alkylamino, (10″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, 2-oxo-1-pyrrolidinyl and2-oxo-1-piperidinyl, (11″) phenyl-C₁₋₄alkyl, (12″) C₃₋₇cycloalkyl, (13″)carboxyl, (14″) C₁₋₄alkoxy-carbonyl, (15″) C₇₋₁₀aralkyloxy-carbonyl,(16″) carbamoyl, (17″) mono-C₁₋₄alkyl-carbamoyl, (18″)di-C₁₋₄alkyl-carbamoyl, (19″) C₁₋₄alkyl which may be substituted with ahalogen atom or C₁₋₄alkoxy, (20″) C₁₋₄alkoxy which may be substitutedwith a halogen atom or C₁₋₄alkoxy, (21″) C₁₋₄alkylenedioxy, (22″)formyl, (23″) C₂₋₄alkanoyl, (24″) C₁₋₄alkylsulfonyl, (25″)C₁₋₄alkylsulfinyl, (26″) sulfamoyl, (27″) mono-C₁₋₄alkylsulfamoyl, (28″)di-C₁₋₄alkylsulfamoyl, (29″) C₆₋₁₄aryl (which may be substituted with asubstituent selected from (1′″) halogen, (2′″) nitro, (3′″) cyano, (4′″)hydroxyl group, (5′″) thiol, (6′″) C₁₋₄alkylthio, (7′″) amino, (8′″)mono-C₁₋₄alkylamino, (9′″) di-C₁₋₄alkylamino, (10′″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (11′″)phenyl-C₁₋₄alkyl, (12′″) C₃₋₇cycloalkyl, (13′″) carboxyl group, (14′″)C₁₋₄alkoxy-carbonyl, (15′″) C₇₋₁₀aralkyloxy-carbonyl, (16′″) carbamoyl,(17′″) mono-C₁₋₄alkyl-carbamoyl, (18′″) di-C₁₋₄alkyl-carbamoyl, (19′″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(20′″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (21′″) C₁₋₄alkylenedioxy, (22′″) formyl, (23′″)C₂₋₄alkanoyl, (24′″) C₁₋₄alkylsulfonyl, (25′″) C₁₋₄alkylsulfinyl, (26′″)sulfamoyl, (27′″) mono-C₁₋₄alkylsulfamoyl, (28′″) di-C₁₋₄alkylsulfamoyland (29′″) 5- to 6-membered aromatic monocyclic heterocyclic group), or(30″) 5- to 8-membered aromatic heterocyclic group or saturated orunsaturated non-aromatic heterocyclic group containing at least one of 1to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom (said heterocyclic group may have 1 to 3 substituentsselected from (1′″) halogen, (2′″) nitro, (3′″) cyano, (4′″) oxo, (5′″)hydroxyl group, (6′″) thiol, (7′″) C₁₋₄alkylthio, (8′″) amino, (9′″)mono-C₁₋₄alkylamino, (10′″) di-C₁₋₁₄alkylamino, (11′″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (12′″)phenyl-C₁₋₄alkyl, (13′″) C₃₋₇cycloalkyl, (14′″) carboxyl, (15′″)C₁₋₄alkoxy-carbonyl, (16′″) C₇₋₁₀aralkyloxy-carbonyl, (17′″) carbamoyl,(18′″) mono-C₁₋₄alkyl-carbamoyl, (19′″) di-C₁₋₄alkyl-carbamoyl, (20′″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(21′″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (22′″) C₁₋₄alkylenedioxy, (23′″) formyl, (24′″)C₂₋₄alkanoyl, (25′″) C₁₋₄alkylsulfonyl and (26′″) C₁₋₄alkylsulfinyl)(hereinafter referred to as substituent group E), or (b) a 5- to8-membered heterocyclic group containing at least one of 1 to 3 kinds ofheteroatoms selected from oxygen atom, sulfur atom and nitrogen atom,said aromatic heterocyclic group optionally having 1 to 3 substituentsselected from the substituent group E; or (12) a group represented bythe formula —X″″—L—(CH₂)_(n)—M, wherein X″″ represents a bond or aC₁₋₄alkylene group which may have 1 to 3 substituents selected from thesubstituent group D, L represents (a) a bond, (b) C₆₋₁₀aryl which mayhave 1 to 3 substituents selected from the substituent group E, (c) a 5-to 8-membered aromatic heterocyclic group containing at least one of 1to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom (said aromatic heterocyclic group optionally having 1 to 3substituents selected from the substituent group E), (d) —O—, (e) —S—,(f) —CO—NH— or (g) —NH—CO—, n is an integer of 0 to 3, and M representsan amino group, guanidino group, sulfamoyl group, carbamoyl group orhydroxyl group, X represents: (1) —(CH₂)_(f1)—, wherein f1 represents aninteger of 1 to 8, (2) —(CH₂)_(g1)—X¹—(CH₂)_(g2)—, wherein g1 and g2 arethe same or different, and represent an integer of 0 to 7, provided thatthe sum of g1 and g2 is 0 to 7, and X¹ represents NH, O, S, SO or SO₂,or (3) —(CH₂)_(h1)—X¹—(CH₂)_(h2)—X²—(CH₂)_(h3)—, wherein h1, h2 and h3are the same or different, and represent an integer of 0 to 6, providedthat the sum of h1, h2 and h3 is 0 to 6, and X¹ and X² each representNH, O, S, SO or SO₂ provided that when h2 is 0, X¹ and/or X² preferablyrepresent NH, A represents (1) amino which may have 1 to 2 substituentsselected from (a) C₁₋₁₀alkyl which may have 1 to 3 substituents selectedfrom (1″) halogen, (2″) nitro, (3″) cyano, (4″) oxo, (5″) hydroxylgroup, (6″) thiol, (7″) C₁₋₄alkylthio, (8″) amino, (9″)mono-C₁₋₄alkylamino, (10″) di-C₁₋₄alkylamino, (11″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (12″)phenyl-C₁₋₄alkyl, (13″) C₃₋₇cycloalkyl, (14″) carboxyl, (15″)C₁₋₄alkoxy-carbonyl, (16″) C₇₋₁₀aralkyloxy-carbonyl, (17″) carbamoyl,(18″) mono-C₁₋₄alkyl-carbamoyl, (19″) di-C₁₋₄alkyl-carbamoyl, (20″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(21″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (22″) C₁₋₄alkylenedioxy, (23″) formyl, (24″) C₂₋₄alkanoyl,(25″) C₁₋₄alkylsulfonyl and (26″) C₁₋₄alkylsulfinyl (hereinafterreferred to as substituent group F), (b) C₃₋₈cycloalkyl which may have 1to 3 substituents selected from the substituent group F, (c)C₂₋₁₀alkenyl which may have 1 to 3 substituents selected from thesubstituent group F, (d) C₃₋₈cycloalkenyl which may have 1 to 3substituents selected from the substituent group F, (e) C₂₋₁₀alkynylwhich may have 1 to 3 substituents selected from the substituent groupF, (f) C₆₋₁₄aryl which may have 1 to 3 substituents selected from thesubstituent group F, (g) C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group F, (h)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group F, (i) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group F, (j) a 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom,which may have 1 to 3 substituents selected from the substituent groupF, (k) acyl selected from formyl, C₁₋₁₀alkyl-carbonyl,C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup F, and (l) acyl wherein a 5- to 8-membered aromatic heterocyclicgroup or saturated or unsaturated non-aromatic heterocyclic groupcontaining at least one of 1 to 3 kinds of heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom has been bound to carbonyl orsulfonyl (said acyl optionally having 1 to 3 substituents selected fromthe substituent group F); or (2) 5- or 6-membered cyclic amino which mayhave 1 to 3 substituents selected from (a) halogen, (b) nitro, (c)cyano, (d) hydroxyl group, (e) thiol, (f) amino, (g) carboxyl, (h)optionally halogenated C₁₋₄alkyl, (i) optionally halogenated C₁₋₄alkoxy,(j) formyl, (k) C₂₋₄alkanoyl and (l) C₁₋₄alkylsulfonyl; or (3) aheterocyclic group formed by removing one hydrogen atom from a 5- to8-membered aromatic monocyclic heterocyclic ring or saturated orunsaturated non-aromatic monocyclic heterocyclic ring containing onenitrogen atom and one to three kinds of 1 to 4 heteroatoms selected froman oxygen atom, a sulfur atom and a nitrogen atom or by removing onehydrogen atom from a ring wherein 2 or 3 the same or different ringsselected from the above monocyclic rings have been condensed (saidheterocyclic group optionally having 1 to 3 substituents selected fromthe substituent group F), R² and R³ each represents (1) C₁₋₁₀alkyl whichmay have 1 to 3 substituents selected from the substituent group D; (2)C₃₋₈cycloalkyl which may have 1 to 3 substituents selected from thesubstituent group D; (3) C₂₋₁₀alkenyl which may have 1 to 3 substituentsselected from the substituent group D; (4) C₃₋₈cycloalkenyl which mayhave 1 to 3 substituents selected from the substituent group D; (5)C₂₋₁₀alkynyl which may have 1 to 3 substituents selected from thesubstituent group D; (6) C₆₋₁₄aryl which may have 1 to 3 substituentsselected from the substituent group D; (7) C₆₋₁₄aryl-C₁₋₆alkyl which mayhave 1 to 3 substituents selected from the substituent group D; (8)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group D; (9) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group D; (10) a grouprepresented by the formula —X′″—(CH₂)_(n)—J, wherein X′″ representsC₁₋₄alkylene or C₂₋₄alkenylene, G represents a bond, —O—, —S—, —CO—NH—or —NH—CO—, n is an integer of 0 to 3, and J represents (a) C₆₋₁₄arylwhich may have 1 to 3 substituents selected from the substituent group Eor (b) a 5- to 8-membered aromatic heterocyclic group which may have atleast one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom (said aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup E), or (11) a group represented by the formula —X″″—L—(CH₂)_(n)—M,wherein X″″ represents a bond or C₁₋₄alkylene which may have 1 to 3substituents selected from the substituent group D, and L represents (a)a bond, (b) C₆₋₁₀aryl which may have 1 to 3 substituents selected fromthe substituent group E, (c) a 5- to 8-membered aromatic heterocyclicgroup containing at least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom (said aromaticheterocyclic group optionally having 1 to 3 substituents selected fromthe substituent group E), (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—,n is an integer of 0 to 3, M represents an amino group, guanidino group,sulfamoyl group, carbamoyl group or hydroxyl group; and rings B and Ceach represent a benzene ring which may further have 1 to 4 substituentsselected from (1) C₁₋₁₀alkyl which may have 1 to 3 substituents selectedfrom the substituent group D; (2) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group D; (3) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupD; (4) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group D; (5) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group D; (6) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group D; (7)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group D; (8) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group D; (9)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group D; (10) a heterocyclic group formed by removingone hydrogen atom from a 5- to 8-membered aromatic monocyclicheterocyclic ring or saturated or unsaturated non-aromatic monocyclicheterocyclic ring containing at least 1 of one to three kinds ofheteroatoms selected from oxygen atom, sulfur atom and nitrogen atom orby removing one hydrogen atom from a ring wherein 2 or 3 of the same ordifferent rings selected from the above monocyclic rings and 5- to8-membered cyclic hydrocarbons have been fused (said heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup D); (11) a halogen atom; (12) amino which may have 1 to 2substituents selected from (a) C₁₋₁₀alkyl which may have 1 to 3substituents selected from the substituent group F, (b) C₃₋₈cycloalkylwhich may have 1 to 3 substituents selected from the substituent groupF, (c) C₂₋₁₀alkenyl which may have 1 to 3 substituents selected from thesubstituent group F, (d) C₃₋₈cycloalkenyl which may have 1 to 3substituents selected from the substituent group F, (e) C₂₋₁₀alkynylwhich may have 1 to 3 substituents selected from the substituent groupF, (f) C₆₋₁₄aryl which may have 1 to 3 substituents selected from thesubstituent group F, (g) C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group F, (h)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group F, (i) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group F, (j) a 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom,which may have 1 to 3 substituents selected from the substituent groupF, (k) acyl selected from formyl, C₁₋₁₀alkyl-carbonyl,C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup F), and (l) acyl groups wherein a 5- to 8-membered aromaticheterocyclic group or saturated or unsaturated non-aromatic heterocyclicgroup containing at least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom has been bound tocarbonyl or sulfonyl (said acyl optionally having 1 to 3 substituentsselected from the substituent group F); (13) 5- or 6-membered cyclicamino which may have 1 to 3 substituents selected from (a) halogen, (b)nitro, (c) cyano, (d) hydroxyl group, (e) thiol, (f) amino, (g)carboxyl, (h) optionally halogenated C₁₋₄alkyl, (i) optionallyhalogenated C₁₋₄alkoxy, (j) formyl, (k) C₂₋₄alkanoyl and (l)C₁₋₄alkylsulfonyl; (14) a group represented by the formula: R⁶—Y—(wherein Y is O, S, S(O) or S(O)₂, and R⁶ is (i) C₁₋₁₀alkyl which mayhave 1 to 3 substituents selected the substituent group D; (ii)C₃₋₈cycloalkyl which may have 1 to 3 substituents selected from thesubstituent group D; (iii) C₂₋₁₀alkenyl which may have 1 to 3substituents selected from the substituent group D; (iv)C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected from thesubstituent group D; (v) C₂₋₁₀alkynyl which may have 1 to 3 substituentsselected from the substituent group D; (vi) C₆₋₁₄aryl which may have 1to 3 substituents selected from the substituent group D; (vii)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group D; (viii) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group D; (ix)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group D; or (x) a heterocyclic group formed by removingone hydrogen atom from a 5- to 8-membered aromatic monocyclicheterocyclic ring or saturated or unsaturated non-aromatic monocyclicheterocyclic ring containing at least 1 of one to three kinds ofheteroatoms selected from oxygen atom, sulfur atom and nitrogen atom orby removing one hydrogen atom from a ring wherein 2 or 3 of the same ordifferent rings selected from the above monocyclic rings and 5- to8-membered cyclic hydrocarbons have been fused (said heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup D)); (15) cyano group; (16) acyl selected from formyl,C₁₋₁₀alkyl-carbonyl, C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄ aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄ aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup F); (17) acyl groups wherein a 5- to 8-membered aromaticheterocyclic group or saturated or unsaturated non-aromatic heterocyclicgroup containing at least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom has been bound tocarbonyl or sulfonyl (said acyl optionally having 1 to 3 substituentsselected from the substituent group F); (18) carboxyl; and (19)carbamoyl which may have 1 to 2 substituents selected from (a)C₁₋₁₀alkyl which may have 1 to 3 substituents selected from thesubstituent group F, (b) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group F, (c) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupF, (d) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group F, (e) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group F, (f) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group F, (g)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group F, (h) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group F, (i)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group F and (j) a 5- to 8-membered aromatic heterocyclicgroup or saturated or unsaturated non-aromatic heterocyclic groupcontaining at least one of 1 to 3 kinds of heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom, which may have 1 to 3substituents selected from the substituent group F; or a salt thereof,provided that4′-[[(methoxyacetyl)methylamino]methyl]-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-[1,1′-biphenyl]-4-carboxamideis excluded.
 3. A compound represented by the formula:

wherein each symbol is as defined in claim 2, or a salt thereof.
 4. Acompound represented by the formula:

wherein each symbol is as defined in claim 2, or a salt thereof.
 5. Acompound represented by the formula:

wherein each symbol is as defined in claim 2, or a salt thereof.
 6. Thecompound according to claim 2, wherein the group represented by theformula:

is a group represented by the formula:

wherein R¹ represents (1) hydrogen atom, (2) C₁₋₁₀alkyl, (3)C₃₋₈cycloalkyl, (4) C₂₋₁₀alkenyl, (5) C₃₋₈cycloalkenyl, (6)C₂₋₁₀alkynyl, (7) C₆₋₁₄aryl, (8) C₆₋₁₄aryl-C₁₋₆alkyl, (9)di-C₆₋₁₄aryl-C₁₋₆alkyl, (10) tri-C₆₋₁₄aryl-C₁₋₆alkyl, (11) a grouprepresented by the formula —X′″—G—(CH₂)_(n)—J, wherein X′″ represents aC₁₋₄alkylene group or C₂₋₄alkenylene group, G represents a bond, —O—,—S—, —CO—NH— or —NH—CO—, n is an integer of 0 to 3, J represents (a)C₆₋₁₄aryl or (b) a 5- to 8-membered aromatic heterocyclic groupcontaining at least one of 1 to 3 kinds of heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom, or (12) a group representedby the formula —X″″—L—(CH₂)_(n)—M, wherein X″″ represents a bond or aC₁₋₄alkylene group, L represents (a) a bond, (b) C₆₋₁₀aryl, (c) a 5- to8-membered aromatic heterocyclic group containing at least one of 1 to 3kinds of heteroatoms selected from oxygen atom, sulfur atom and nitrogenatom, (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—, n is an integer of 0to 3, and M represents an amino group, guanidino group, sulfamoyl group,carbamoyl group or hydroxyl group, X′ represents C₁₋₆alkylene, R⁴ and R⁵each represents hydrogen atom or C₁₋₆alkyl (which may have 1 to 3substituents selected from (i) halogen, (ii) nitro, (iii) cyano, (iv)hydroxyl group, (v) thiol, (vi) C₁₋₄alkylthio, (vii) amino, (viii)mono-C₁₋₄alkylamino, (ix) di-C₁₋₄alkylamino, (x) 5- to 6-membered cyclicamino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (xi) carboxyl, (xii)C₁₋₄alkoxy-carbonyl, (xiii) C₇₋₁₀aralkyloxy-carbonyl, (xiv) carbamoyl,(xv) mono-C₁₋₄alkyl-carbamoyl, (xvi) di-C₁₋₄alkyl-carbamoyl, (xvii)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(xviii) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (xix) C₁₋₄alkylenedioxy, (xx) phenyl-C₁₋₄alkyl, (xxi)C₃₋₇cycloalkyl, (xxii) formyl, (xxiii) C₂₋₄alkanoyl, (xxiv)C₁₋₄alkylsulfonyl and (xxv) C₁₋₄alkylsulfinyl), and R⁴ and R⁵ togetherwith their adjacent nitrogen atom may be bound to each other to form a3- to 8-membered cyclic amino group.
 7. The compound according to claim6, wherein each of R⁴ and R⁵ is hydrogen atom.
 8. The compound accordingto claim 6, wherein R⁴ and R⁵ are bound to each other to form a 3- to8-membered saturated nitrogen-containing heterocyclic ring.
 9. Thecompound according to claim 2, wherein the group represented by theformula:

is a group represented by the formula:

wherein X″ represents a bond or C₁₋₄alkylene, and rings D and E eachrepresents a 3- to 8-membered saturated nitrogen-containing heterocyclicring.
 10. The compound according to claim 2, wherein R² is a grouprepresented by the formula —X′″—G—(CH₂)_(n)—J wherein X′″ represents aC₁₋₄alkylene group or C₂₋₄alkenylene group, G represents a bond, —O—,—S—, —CO—NH— or —NH—CO—, n is an integer of 0 to 3, J represents (a) aC₆₋₁₄aryl group (which may have 1 to 3 substituents selected from (i)halogen, (ii) hydroxyl group, (iii) C₁₋₄alkyl which may be substitutedwith a halogen atom or C₁₋₄alkoxy, (iv) C₁₋₄alkoxy which may besubstituted with a halogen atom or C₁₋₄alkoxy and (v) sulfamoyl), or (b)a 5- to 8-membered aromatic heterocyclic group containing at least oneof 1 to 3 kinds of heteroatoms selected from oxygen atom, sulfur atomand nitrogen atom.
 11. The compound according to claim 2, wherein R² isa group represented by the formula —X″″—L—(CH₂)_(n)—M wherein X″″represents a bond or a C₁₋₄alkylene group, L represents (a) a bond, (b)C₆₋₁₄aryl, (c) a 5- to 8-membered aromatic heterocyclic group containingat least one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom, (d) —O—, (e) —S—, (f) —CO—NH— or (g)—NH—CO—, n is an integer of 0 to 3, and M represents an amino group,guanidino group, sulfamoyl group, carbamoyl group or hydroxyl group. 12.The compound according to claim 2, wherein R³ represents a grouprepresented by the formula —(CH₂)_(p)—T, wherein p is an integer of 1 to6, T represents (a) C₆₋₁₄aryl (which may have 1 to 3 substituentsselected from (i) halogen, (ii) hydroxyl group, (iii) phenyl-C₁₋₄alkyl,(iv) carboxyl, (v) C₁₋₄alkoxy-carbonyl, (vi) C₁₋₄alkyl which may besubstituted with a halogen atom or C₁₋₄alkoxy, (vii) C₁₋₄alkoxy whichmay be substituted with a halogen atom or C₁₋₄alkoxy, (viii)C₁₋₄alkylenedioxy, (ix) sulfamoyl, (x) C₁₋₄alkylsulfamoyl, (xi)di-C₁₋₄alkylsulfamoyl and (xii) a 5- to 8-membered aromatic heterocyclicgroup or saturated or unsaturated non-aromatic heterocyclic groupcontaining at least one of 1 to 3 kinds of heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom, or (b) a 5- to 8-memberedaromatic heterocyclic group containing at least one of 1 to 3 kinds ofheteroatoms selected from oxygen atom, sulfur atom and nitrogen atom.13. The compound according to claim 12, wherein T is phenyl groupsubstituted with hydroxyl group, sulfamoyl, C₁₋₄alkylsulfamoyl ordi-C₁₋₄alkylsulfamoyl. 14.3′-{[{2-[4-(Aminosulfonyl)phenyl]ethyl}(4-phenylbutanoyl)amino]methyl}-N-[2-(1-pyrrolidinyl)ethyl]-[1,1′-biphenyl]-3-carboxamideor a salt thereof. 15.3′-({{2-[4-(Aminosulfonyl)phenyl]ethyl}-[(benzyloxy)acetyl]amino}methyl)-N-[2-(1-pyrrolidinyl)-ethyl][1,1′-biphenyl]-3-carboxamideor a salt thereof. 16.N-(2-Aminoethyl)-3′-{[[3-({[amino(imino)methyl]-amino}methyl)benzoyl](1-naphthylmethyl)amino]methyl}-1,1′-biphenyl]-2-carboxamideor a salt thereof. 17.N-(2-Aminoethyl)-3′-{[[4-(aminosulfonyl)benzoyl]-(1-naphthylmethyl)amino]methyl}-1,1′-biphenyl-2-carboxamideor a salt thereof.
 18. A prodrug of the compound according to claim 1 or2 or a salt thereof.
 19. A pharmaceutical composition comprising acompound represented by the formula (I):

wherein R¹ is (1) hydrogen atom; (2) C₁₋₁₀alkyl which may have 1 to 3substituents selected from (1′) halogen atom, (2′) nitro, (3′) cyano,(4′) oxo, (5′) hydroxyl group, (6′) thiol, (7′) C₁₋₄alkylthio, (8′)amino group, (9′) mono-C₁₋₄alkylamino, (10′) di-C₁₋₄alkylamino, (11′) 5-to 6-membered cyclic amino selected from tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole,2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinyl, (12′) phenyl-C₁₋₄alkyl,(13′) C₃₋₇cycloalkyl, (14′) carboxyl, (15′) C₁₋₄alkoxy-carbonyl, (16′)C₇₋₁₀aralkyloxy-carbonyl, (17′) carbamoyl, (18′)mono-C₁₋₄alkylcarbamoyl, (19′) di-C₁₋₄alkylcarbamoyl, (20′) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (21′)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(22′) C₁₋₄alkylenedioxy, (23′) formyl, (24′) C₂₋₄alkanoyl, (25′)C₁₋₄alkylsulfonyl, (26′) C₁₋₄alkylsulfinyl, (27′) sulfamoyl, (28′)mono-C₁₋₄alkylsulfamoyl, (29′) di-C₁₋₄alkylsulfamoyl, (30′) C₆₋₁₄aryl(which may be substituted with a substituent(s) selected from (1″)halogen, (2″) nitro, (3″) cyano, (4″) hydroxyl group, (5″) thiol, (6″)C₁₋₄alkylthio, (7″) amino, (8″) mono-C₁₋₄alkylamino, (9″)di-C₁₋₄alkylamino, (10″) 5- to 6-membered cyclic amino selected fromtetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole and imidazole, (11″) phenyl-C₁₋₄alkyl, (12″) C₃₋₇cycloalkyl,(13″) carboxyl group, (14″) C₁₋₄alkoxy-carbonyl, (15″)C₇₋₁₀aralkyloxy-carbonyl, (16″) carbamoyl, (17″)mono-C₁₋₄alkyl-carbamoyl, (18″) di-C₁₋₄alkyl-carbamoyl, (19″) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (20″)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(21″) C₁₋₄alkylenedioxy, (22″) formyl, (23″) C₂₋₄alkanoyl, (24″)C₁₋₄alkylsulfonyl, (25″) C₁₋₄alkylsulfinyl, (26″) sulfamoyl, (27″)mono-C₁₋₄alkylsulfamoyl, (28″) di-C₁₋₄alkylsulfamoyl and (29″) 5- to6-membered aromatic monocyclic heterocyclic group), and (31′) 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom(said heterocyclic group may have 1 to 3 substituents selected from (1″)halogen, (2″) nitro, (3″) cyano, (4″) oxo, (5″) hydroxyl group, (6″)thiol, (7″) C₁₋₄alkylthio, (8″) amino, (9″) mono-C₁₋₄alkylamino, (10″)di-C₁₋₄alkylamino, (11″) 5- to 6-membered cyclic amino selected fromtetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole and imidazole, (12″) phenyl-C₁₋₄alkyl, (13″) C₃₋₇cycloalkyl,(14″) carboxyl, (15″) C₁₋₄alkoxy-carbonyl, (16″)C₇₋₁₀aralkyloxy-carbonyl, (17″) carbamoyl, (18″)mono-C₁₋₄alkyl-carbamoyl, (19″) di-C₁₋₄alkyl-carbamoyl, (20″) C₁₋₄alkylwhich may be substituted with a halogen atom or C₁₋₄alkoxy, (21″)C₁₋₄alkoxy which may be substituted with a halogen atom or C₁₋₄alkoxy,(22″) C₁₋₄alkylenedioxy, (23″) formyl, (24″) C₂₋₄alkanoyl, (25″)C₁₋₄alkylsulfonyl, and (26″) C₁₋₄alkylsulfinyl)(hereinafter referred toas substituent group A); (3) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group A; (4) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupA; (5) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group A; (6) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group A; (7) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group A; (8)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group A; (9) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group A; (10)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (11) a group represented by the formula—X′″—G—(CH₂)_(n)—J wherein X′″ represents C₁₋₄alkylene orC₂₋₄alkenylene, G is a bond, —O—, —S—, —CO—NH— or —NH—CO—, n is aninteger of 0 to 3, J represents (a) C₆₋₁₄aryl (which may have 1 to 3substituents selected from (1″) halogen, (2″) nitro, (3″) cyano, (4″)hydroxyl group, (5″) thiol, (6″) C₁₋₄alkylthio, (7″) amino, (8″)mono-C₁₋₄alkylamino, (9″) di-C₁₋₄alkylamino, (10″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, 2-oxo-1-pyrrolidinyl and2-oxo-1-piperidinyl, (11″) phenyl-C₁₋₄alkyl, (12″) C₃₋₇cycloalkyl, (13″)carboxyl, (14″) C₁₋₄alkoxy-carbonyl, (15″) C₇₋₁₀aralkyloxy-carbonyl,(16″) carbamoyl, (17″) mono-C₁₋₄alkyl-carbamoyl, (18″)di-C₁₋₄alkyl-carbamoyl, (19″) C₁₋₄alkyl which may be substituted with ahalogen atom or C₁₋₄alkoxy, (20″) C₁₋₄alkoxy which may be substitutedwith a halogen atom or C₁₋₄alkoxy, (21″) C₁₋₄alkylenedioxy, (22″)formyl, (23″) C₂₋₄alkanoyl, (24″) C₁₋₄alkylsulfonyl, (25″)C₁₋₄alkylsulfinyl, (26″) sulfamoyl, (27″) mono-C₁₋₄alkylsulfamoyl, (28″)di-C₁₋₄alkylsulfamoyl, (29″) C₆₋₁₄aryl (which may be substituted with asubstituent(s) selected from (1′″) halogen, (2′″) nitro, (3′″) cyano,(4′″) hydroxyl group, (5′″) thiol, (6′″) C₁₋₄alkylthio, (7′″) amino,(8′″) mono-C₁₋₄alkylamino, (9′″) di-C₁₋₄alkylamino, (10′″) 5- to6-membered cyclic amino selected from tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole and imidazole, (11′″)phenyl-C₁₋₄alkyl, (12′″) C₃₋₇cycloalkyl, (13′″) carboxyl group, (14′″)C₁₋₄alkoxy-carbonyl, (15′″) C₇₋₁₀aralkyloxy-carbonyl, (16′″) carbamoyl,(17′″) mono-C₁₋₄alkyl-carbamoyl, (18′″) di-C₁₋₄alkyl-carbamoyl, (19′″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(20′″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (21′″) C₁₋₄alkylenedioxy, (22′″) formyl, (23′″)C₂₋₄alkanoyl, (24′″) C₁₋₄alkylsulfonyl, (25′″) C₁₋₄alkylsulfinyl, (26′″)sulfamoyl, (27′″) mono-C₁₋₄alkylsulfamoyl, (28′″) di-C₁₋₄alkylsulfamoyl,and (29′″) 5- to 6-membered aromatic monocyclic heterocyclic group), and(30″) 5- to 8-membered aromatic heterocyclic group or saturated orunsaturated non-aromatic heterocyclic group containing at least one of 1to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom (said heterocyclic group may have 1 to 3 substituentsselected from (1′″) halogen, (2′″) nitro, (3′″) cyano, (4′″) oxo, (5′″)hydroxyl group, (6′″) thiol, (7′″) C₁₋₄alkylthio, (8′″) amino, (9′″)mono-C₁₋₄alkylamino, (10′″) di-C₁₋₄alkylamino, (11′″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (12′″)phenyl-C₁₋₄alkyl, (13′″) C₃₋₇cycloalkyl, (14′″) carboxyl, (15′″)C₁₋₄alkoxy-carbonyl, (16′″) C₇₋₁₀aralkyloxy-carbonyl, (17′″) carbamoyl,(18′″) mono-C₁₋₄alkyl-carbamoyl, (19′″) di-C₁₋₄alkyl-carbamoyl, (20′″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(21′″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (22′″) C₁₋₄alkylenedioxy, (23′″) formyl, (24′″)C₂₋₄alkanoyl, (25′″) C₁₋₄alkylsulfonyl and (26′″) C₁₋₄alkylsulfinyl)(hereinafter referred to as substituent group B), or (b) a 5- to8-membered aromatic heterocyclic group containing at least one of 1 to 3kinds of heteroatoms selected from oxygen atom, sulfur atom and nitrogenatom (said aromatic heterocyclic group optionally having 1 to 3substituents selected from the substituent group B); or (12) a grouprepresented by the formula —X″″—L—(CH₂)_(n)—M wherein X″″ represents abond or a C₁₋₄alkylene group which may have 1 to 3 substituents selectedfrom the substituent group A, L represents (a) a bond, (b) C₆₋₁₀arylwhich may have 1 to 3 substituents selected from the substituent groupB, (c) a 5- to 8-membered aromatic heterocyclic group containing atleast one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom (said aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup B), (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—CO—, n is an integerof 0 to 3, and M represents amino group, guanidino group, sulfamoylgroup, carbamoyl group or hydroxyl group, X represents: (1)—(CH₂)_(f1)—, wherein f1 represents an integer of 1 to 12, (2)—(CH₂)_(g1)—X¹—(CH₂)_(g2)—, wherein g1 and g2 are the same or different,and represent an integer of 0 to 11, provided that the sum of g1 and g2is 0 to 11, and X¹ represents NH, O, S, SO or SO₂, or (3)—(CH₂)_(h1)—X¹—(CH₂)_(h2)—X²—(CH₂)_(h3)— wherein h1, h2 and h3 are thesame or different, and represent an integer of 0 to 10, provided thatthe sum of h1, h2 and h3 is 0 to 10, and X¹ and X² each represents NH,O, S, SO or SO₂ provided that when h2 is 0, X¹ and/or X² preferablyrepresent NH, A represents (1) amino which may have 1 to 2 substituentsselected from (a) C₁₋₁₀alkyl which may have 1 to 3 substituents selectedfrom (1″) halogen, (2″) nitro, (3″) cyano, (4″) oxo, (5″) hydroxylgroup, (6″) thiol, (7″) C₁₋₄alkylthio, (8″) amino, (9″)mono-C₁₋₄alkylamino, (10″) di-C₁₋₄alkylamino, (11″) 5- to 6-memberedcyclic amino selected from tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole and imidazole, (12″)phenyl-C₁₋₄alkyl, (13″) C₃₋₇cycloalkyl, (14″) carboxyl, (15″)C₁₋₄alkoxy-carbonyl, (16″) C₇₋₁₀aralkyloxy-carbonyl, (17″) carbamoyl,(18″) mono-C₁₋₄alkyl-carbamoyl, (19″) di-C₁₋₄alkyl-carbamoyl, (20″)C₁₋₄alkyl which may be substituted with a halogen atom or C₁₋₄alkoxy,(21″) C₁₋₄alkoxy which may be substituted with a halogen atom orC₁₋₄alkoxy, (22″) C₁₋₄alkylenedioxy, (23″) formyl, (24″) C₂₋₄alkanoyl,(25″) C₁₋₄alkylsulfonyl and (26″) C₁₋₄alkylsulfinyl (hereinafterreferred to as substituent group C), (b) C₃₋₈cycloalkyl which may have 1to 3 substituents selected from the substituent group C, (c)C₂₋₁₀alkenyl which may have 1 to 3 substituents selected from thesubstituent group C, (d) C₃₋₈cycloalkenyl which may have 1 to 3substituents selected from the substituent group C, (e) C₂₋₁₀alkynylwhich may have 1 to 3 substituents selected from the substituent groupC, (f) C₆₋₁₄aryl which may have 1 to 3 substituents selected from thesubstituent group C, (g) C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group C, (h)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group C, (i) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group C, (j) a 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom,which may have 1 to 3 substituents selected from the substituent groupC, (k) acyl selected from formyl, C₁₋₁₀alkyl-carbonyl,C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup C), and (1) acyl groups wherein a 5- to 8-membered aromaticheterocyclic group or saturated or unsaturated non-aromatic heterocyclicgroup containing at least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom has been bound tocarbonyl or sulfonyl (said acyl optionally having 1 to 3 substituentsselected from the substituent group C); or (2) 5- or 6-membered cyclicamino which may have 1 to 3 substituents selected from (a) halogen, (b)nitro, (c) cyano, (d) hydroxyl group, (e) thiol, (f) amino, (g)carboxyl, (h) optionally halogenated C₁₋₄alkyl, (i) optionallyhalogenated C₁₋₄alkoxy, (j) formyl, (k) C₂₋₄alkanoyl and (l)C₁₋₄alkylsulfonyl; or (3) a heterocyclic group formed by removing onehydrogen atom from a 5- to 8-membered aromatic monocyclic heterocyclicring or saturated or unsaturated non-aromatic monocyclic heterocyclicring containing one nitrogen atom and one to three kinds of 1 to 4heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom orby removing one hydrogen atom from a ring wherein 2 or 3 of the same ordifferent rings selected from the above monocyclic rings have been fused(said heterocyclic group optionally having 1 to 3 substituents selectedfrom the substituent group C), R² represents (1) C₁₋₁₀alkyl which mayhave 1 to 3 substituents selected from the substituent group A; (2)C₃₋₈cycloalkyl which may have 1 to 3 substituents selected from thesubstituent group A; (3) C₂₋₁₀alkenyl which may have 1 to 3 substituentsselected from the substituent group A; (4) C₃₋₈cycloalkenyl which mayhave 1 to 3 substituents selected from the substituent group A; (5)C₂₋₁₀alkynyl which may have 1 to 3 substituents selected from thesubstituent group A; (6) C₆₋₁₄aryl which may have 1 to 3 substituentsselected from the substituent group A; (7) C₆₋₁₄aryl-C₁₋₆alkyl which mayhave 1 to 3 substituents selected from the substituent group A; (8)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (9) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group A; (10) a grouprepresented by the formula —X′″—G—(CH₂)_(n)—J, wherein X′″ representsC₁₋₄alkylene or C₂₋₄alkenylene, G represents a bond, —O—, —S—, —CO—NH—or —NH—CO—, n is an integer of 0 to 3, and J represents (a) C₆₋₁₄aryl(which may have 1 to 3 substituents selected from the substituent groupB) or (b) a 5- to 8-membered aromatic heterocyclic group which may haveat least one of 1 to 3 kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom (said aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup B); (11) a group represented by the formula —X″″—L—(CH₂)_(n)—M,wherein X″″ represents a bond or C₁₋₄alkylene which may have 1 to 3substituents selected from the substituent group A, and L represents (a)a bond, (b) C₆₋₁₀aryl which may have 1 to 3 substituents selected fromthe substituent group B, (c) a 5- to 8-membered aromatic heterocyclicgroup containing at least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom (said aromaticheterocyclic group optionally having 1 to 3 substituents selected fromthe substituent group B), (d) —O—, (e) —S—, (f) —CO—NH— or (g) —NH—O—, nis an integer of 0 to 3, M represents an amino group, guanidino group,sulfamoyl group, carbamoyl group or hydroxyl group; or (12) amino whichmay have 1 to 2 substituents selected from (a) C₁₋₁₀alkyl which may have1 to 3 substituents selected from the substituent group C, (b)C₃₋₈cycloalkyl which may have 1 to 3 substituents selected from thesubstituent group C, (c) C₂₋₁₀alkenyl which may have 1 to 3 substituentsselected from the substituent group C, (d) C₃₋₈cycloalkenyl which mayhave 1 to 3 substituents selected from the substituent group C, (e)C₂₋₁₀alkynyl which may have 1 to 3 substituents selected from thesubstituent group C, (f) C₆₋₁₄aryl which may have 1 to 3 substituentsselected from the substituent group C, (g) C₆₋₁₄aryl-C₁₋₆alkyl which mayhave 1 to 3 substituents selected from the substituent group C, (h)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group C, (i) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group C, (j) a 5- to8-membered aromatic heterocyclic group or saturated or unsaturatednon-aromatic heterocyclic group containing at least one of 1 to 3 kindsof heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom,which may have 1 to 3 substituents selected from the substituent groupC, (k) acyl selected from formyl, C₁₋₁₀alkyl-carbonyl,C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup C), and (l) acyl groups wherein a 5- to 8-membered aromaticheterocyclic group or saturated or unsaturated non-aromatic heterocyclicgroup containing a least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom has been bound to acarbonyl or sulfonyl group (said acyl optionally having 1 to 3substituents selected from the substituent group C), R³ represents (1)C₁₋₁₀alkyl which may have 1 to 3 substituents selected the substituentgroup A; (2) C₃₋₈cycloalkyl which may have 1 to 3 substituents selectedfrom the substituent group A; (3) C₂₋₁₀alkenyl which may have 1 to 3substituents selected from the substituent group A; (4) C₃₋₈cycloalkenylwhich may have 1 to 3 substituents selected from the substituent groupA; (5) C₂₋₁₀alkynyl which may have 1 to 3 substituents selected from thesubstituent group A; (6) C₆₋₁₄aryl which may have 1 to 3 substituentsselected from the substituent group A; (7) C₆₋₁₄aryl-C₁₋₆alkyl which mayhave 1 to 3 substituents selected from the substituent group A; (8)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (9) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group A; (10) a grouprepresented by the formula —X′″—G—(CH₂)_(n)—J, wherein X′″ representsC₁₋₄alkylene or C₂₋₄alkenylene, G represents a bond, —O—, —S—, —CO—NH—or —NH—CO—, n is an integer of 0 to 3, and J represents (a) a C₆₋₁₄arylgroup (which may have 1 to 3 substituents selected from the substituentgroup B) or (b) a 5- to 8-membered aromatic heterocyclic group which mayhave at least one of 1 to 3 kinds of heteroatoms selected from oxygenatom, sulfur atom and nitrogen atom (said aromatic heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup B); or (11) a group represented by the formula —X″″—L—(CH₂)_(n)—M,wherein X″″ represents a bond or C₁₋₄alkylene which may have 1 to 3substituents selected from the substituent group A, and L represents (a)a bond, (b) C₆₋₁₀aryl (which may have 1 to 3 substituents selected fromthe substituent group B), or (c) a 5- to 8-membered aromaticheterocyclic group containing at least one of 1 to 3 kinds ofheteroatoms selected from oxygen atom, sulfur atom and nitrogen atom(said aromatic heterocyclic group optionally having 1 to 3 substituentsselected from the substituent group B), (d) —O—, (e) —S—, (f) —CO—NH— or(g) —NH—CO—, n is an integer of 0 to 3, M represents amino group,guanidino group, sulfamoyl group, carbamoyl group or hydroxyl group; andrings B and C each represent a benzene ring which may further have 1 to4 substituents selected from (1) C₁₋₁₀alkyl which may have 1 to 3substituents selected the substituent group A; (2) C₃₋₈cycloalkyl whichmay have 1 to 3 substituents selected from the substituent group A; (3)C₂₋₁₀alkenyl which may have 1 to 3 substituents selected from thesubstituent group A; (4) C₃₋₈cycloalkenyl which may have 1 to 3substituents selected from the substituent group A; (5) C₂₋₁₀alkynylwhich may have 1 to 3 substituents selected from the substituent groupA; (6) C₆₋₁₄aryl which may have 1 to 3 substituents selected from thesubstituent group A; (7) C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group A; (8)di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; (9) tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to3 substituents selected from the substituent group A; (10) aheterocyclic group formed by removing one hydrogen atom from a 5- to8-membered aromatic monocyclic heterocyclic ring or saturated orunsaturated non-aromatic monocyclic heterocyclic ring containing atleast 1 of one to three kinds of heteroatoms selected from oxygen atom,sulfur atom and nitrogen atom or by removing one hydrogen atom from aring wherein 2 or 3 of the same or different rings selected from theabove monocyclic rings and 5- to 8-membered cyclic hydrocarbons havebeen fused (said heterocyclic group optionally having 1 to 3substituents selected from the substituent group A); (11) a halogenatom; (12) amino which may have 1 to 2 substituents selected from (a)C₁₋₁₀alkyl which may have 1 to 3 substituents selected from thesubstituent group C, (b) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group C, (c) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupC, (d) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group C, (e) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group C, (f) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group C, (g)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group C, (h) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group C, (i)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group C, (j) a 5- to 8-membered aromatic heterocyclicgroup or saturated or unsaturated non-aromatic heterocyclic groupcontaining at least one of 1 to 3 kinds of heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom, which may have 1 to 3substituents selected from the substituent group C, (k) acyl selectedfrom formyl, C₁₋₁₀alkyl-carbonyl, C₃₋₈cycloalkyl-carbonyl,C₂₋₁₀alkenyl-carbonyl, C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl,C₆₋₁₄aryl-carbonyl, C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,C₁₋₁₀alkylsulfonyl, C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl,C₃₋₈cycloalkenylsulfonyl, C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl,C₆₋₁₄aryl-C₁₋₆alkylsulfonyl, di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl ortri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (said acyl optionally having 1 to 3substituents selected from the substituent group C), and (l) acyl groupswherein a 5- to 8-membered aromatic heterocyclic group or saturated orunsaturated non-aromatic heterocyclic group containing at least one of 1to 3 kinds of heteroatoms selected from oxygen atom, sulfur atom andnitrogen atom has been bound to carbonyl or sulfonyl (said acyloptionally having 1 to 3 substituents selected from the substituentgroup C); (13) 5- or 6-membered cyclic amino which may have 1 to 3substituents selected from (a) halogen, (b) nitro, (c) cyano, (d)hydroxyl group, (e) thiol, (f) amino, (g) carboxyl, (h) optionallyhalogenated C₁₋₄alkyl, (i) optionally halogenated C₁₋₄alkoxy, (j)formyl, (k) C₂₋₄alkanoyl and (l) C₁₋₄alkylsulfonyl; (14) a grouprepresented by the formula: R⁶—Y— (wherein Y is O, S, S(O) or S(O)₂, andR⁶ is (i) C₁₋₁₀alkyl which may have 1 to 3 substituents selected thesubstituent group A; (ii) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group A; (iii) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupA; (iv) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selectedfrom the substituent group A; (v) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group A; (vi) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group A;(vii) C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selectedfrom the substituent group A; (viii) di-C₆₋₁₄aryl-C₁₋₆alkyl which mayhave 1 to 3 substituents selected from the substituent group A; (ix)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group A; or (x) a heterocyclic group formed by removingone hydrogen atom from a 5- to 8-membered aromatic monocyclicheterocyclic ring or saturated or unsaturated non-aromatic monocyclicheterocyclic ring containing at least 1 of one to three kinds ofheteroatoms selected from oxygen atom, sulfur atom and nitrogen atom orby removing one hydrogen atom from a ring wherein 2 or 3 of the same ordifferent rings selected from the above monocyclic rings and 5- to8-membered cyclic hydrocarbons have been fused (said heterocyclic groupoptionally having 1 to 3 substituents selected from the substituentgroup A)); (15) cyano group; (16) acyl selected from formyl,C₁₋₁₀alkyl-carbonyl, C₃₋₈cycloalkyl-carbonyl, C₂₋₁₀alkenyl-carbonyl,C₃₋₈cycloalkenyl-carbonyl, C₂₋₁₀alkynyl-carbonyl, C₆₋₁₄aryl-carbonyl,C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, di-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl,tri-C₆₋₁₄aryl-C₁₋₆alkyl-carbonyl, C₁₋₁₀alkylsulfonyl,C₃₋₈cycloalkylsulfonyl, C₂₋₁₀alkenylsulfonyl, C₃₋₈cycloalkenylsulfonyl,C₂₋₁₀alkynylsulfonyl, C₆₋₁₄arylsulfonyl, C₆₋₁₄aryl-C₁₋₆alkylsulfonyl,di-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl or tri-C₆₋₁₄aryl-C₁₋₆alkylsulfonyl (saidacyl optionally having 1 to 3 substituents selected from the substituentgroup C); (17) acyl groups wherein a 5- to 8-membered aromaticheterocyclic group or saturated or unsaturated non-aromatic heterocyclicgroup containing at least one of 1 to 3 kinds of heteroatoms selectedfrom oxygen atom, sulfur atom and nitrogen atom has been bound tocarbonyl or sulfonyl (said acyl optionally having 1 to 3 substituentsselected from the substituent group C); (18) carboxyl; and (19)carbamoyl which may have 1 to 2 substituents selected from (a)C₁₋₁₀alkyl which may have 1 to 3 substituents selected from thesubstituent group C, (b) C₃₋₈cycloalkyl which may have 1 to 3substituents selected from the substituent group C, (c) C₂₋₁₀alkenylwhich may have 1 to 3 substituents selected from the substituent groupC, (d) C₃₋₈cycloalkenyl which may have 1 to 3 substituents selected fromthe substituent group C, (e) C₂₋₁₀alkynyl which may have 1 to 3substituents selected from the substituent group C, (f) C₆₋₁₄aryl whichmay have 1 to 3 substituents selected from the substituent group C, (g)C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected from thesubstituent group C, (h) di-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3substituents selected from the substituent group C, (i)tri-C₆₋₁₄aryl-C₁₋₆alkyl which may have 1 to 3 substituents selected fromthe substituent group C and (j) a 5- to 8-membered aromatic heterocyclicgroup or saturated or unsaturated non-aromatic heterocyclic groupcontaining at least one of 1 to 3 kinds of heteroatoms selected fromoxygen atom, sulfur atom and nitrogen atom, which may have 1 to 3substituents selected from the substituent group C; provided that (1) acompound represented by the formula:

wherein each symbol has the same meaning as defined above, and (2)4′-[[(methoxyacetyl)methylamino]methyl]-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-[1,1′-biphenyl]-4-carboxamideare excluded, or a salt thereof or a prodrug thereof.
 20. A method forinhibiting vasoconstriction comprising administering an effective amountof a compound of claim 1 to a mammal in need thereof.
 21. A method fortreating hypertension, arteriosclerosis, cardiac hypertrophy, myocardialinfarction or heart failure, comprising administering an effectiveamount of a compound of claim 1 to a mammal in need thereof.
 22. Aprocess for producing the compound according to claim 1 or a saltthereof, which comprises (i) reacting a compound represented by theformula:

wherein each symbol is as defined in claim 1, or a salt thereof, with acompound represented by the formula: R²COOH wherein R² is as defined inclaim 1, or a salt thereof, or a reactive derivative thereof, or (ii)reacting a compound represented by formula:

wherein each symbol is as defined in claim 1, or a salt thereof or areactive derivative thereof, with a compound represented by the formula:

wherein each symbol is as defined in claim 1, or a salt thereof.